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Publications


2016

Osanjo, GO, Oyugi JO, Kibwage IO, Mwanda WO, Ngugi EN, Otieno FC, Ndege W, Child M, Farquhar C, Penner J, Talib Z, Kiarie JN.  2016.  Building capacity in implementation science research training at the University of Nairobi., 2016. Implementation science : IS. 11:30. Abstract

Health care systems in sub-Saharan Africa, and globally, grapple with the problem of closing the gap between evidence-based health interventions and actual practice in health service settings. It is essential for health care systems, especially in low-resource settings, to increase capacity to implement evidence-based practices, by training professionals in implementation science. With support from the Medical Education Partnership Initiative, the University of Nairobi has developed a training program to build local capacity for implementation science.

Ochwoto, M, Kimotho JH, Julius Oyugi, Okoth F, Kioko H, Mining S, Budambula NLM, Giles E, Andonov A, Songok E, Osiowy C.  2016.  Hepatitis B infection is highly prevalent among patients presenting with jaundice in Kenya., 2016. BMC infectious diseases. 16:101. Abstract

Viral hepatitis is a major concern worldwide, with hepatitis A (HAV) and E (HEV) viruses showing sporadic outbreaks while hepatitis B (HBV) and C (HCV) viruses are associated with chronic hepatitis, cirrhosis and hepatocellular carcinoma. The present study determined the proportion, geographic distribution and molecular characterization of hepatitis viruses among patients seeking medical services at hospitals throughout Kenya.

Omollo, K, Boily-Larouche G, Lajoie J, Kimani M, Cheruiyot J, Kimani J, Julius Oyugi, Fowke KR.  2016.  The Impact of Sex Work Interruption on Blood-Derived T Cells in Sex Workers from Nairobi, Kenya., 2016 Mar 16. AIDS research and human retroviruses. Abstract

Unprotected sexual intercourse exposes the female genital tract (FGT) to semen-derived antigens, which leads to a proinflammatory response. Studies have shown that this postcoital inflammatory response can lead to recruitment of activated T cells to the FGT, thereby increasing risk of HIV infection.

Lajoie, J, Boily-Larouche G, Doering K, Cheruiyot J, Julius Oyugi, Broliden K, Kimani J, Fowke KR.  2016.  Improving Adherence to Post-Cervical Biopsy Sexual Abstinence in Kenyan Female Sex Workers., 2016 Jul. American journal of reproductive immunology (New York, N.Y. : 1989). 76(1):82-93. Abstract

Cervical biopsies offer a unique opportunity for studying local immune response. To investigate hormonally induced immune fluctuations in cervical tissues of Kenyan female sex workers, we improved biopsy sampling protocol safety. Here, we report on steps taken to minimize exposure to HIV following two cervical biopsies.

2015

  2015.  Detection of peste des petits ruminants virus in formalin-fixed tissues., 2015 Jan. Tropical animal health and production. 47(1):247-9. Abstract

Peste des petits ruminants virus that causes a highly infectious and often fatal disease of sheep and goats is confirmed by various diagnostic techniques among them being isolation of the virus from cell culture systems, viral ribonucleic acid (RNA) detection by molecular assays, and viral antigen detection by immunocapture enzyme-linked immunosorbent assay (IC ELISA), immunohistochemistry (IHC), and AGAR gel test. Whereas most of the confirmatory diagnostic procedures require pathological samples to be stored frozen to preserve integrity of the peste des petits ruminants (PPR) virus RNA, samples for IHC tests are preserved in 10% formalin. In this study, nine formalin-fixed pathological samples from three goats suspected of PPR were processed for extraction of PPR viral RNA and analyzed for detection with real-time reverse transcription-polymerase chain reaction (qRT-PCR) assay. The results showed that five out of the nine tested samples returned positive for presences PPR viral genome. This study has established that field pathological samples of PPR-suspected cases, collected and stored in 10% formalin for up 2 years, could be used for PPR virus RNA extraction for disease virus confirmation.

Kihu, SM, Gitao GC, Bebora LC, Njenga MJ, Wairire GG, Maingi N, Wahome RG, Oyugi JO, Lutomia E.  2015.  Detection of peste des petits ruminants virus in formalin-fixed tissues., 2015 Jan. Tropical animal health and production. 47(1):247-9. Abstract

Peste des petits ruminants virus that causes a highly infectious and often fatal disease of sheep and goats is confirmed by various diagnostic techniques among them being isolation of the virus from cell culture systems, viral ribonucleic acid (RNA) detection by molecular assays, and viral antigen detection by immunocapture enzyme-linked immunosorbent assay (IC ELISA), immunohistochemistry (IHC), and AGAR gel test. Whereas most of the confirmatory diagnostic procedures require pathological samples to be stored frozen to preserve integrity of the peste des petits ruminants (PPR) virus RNA, samples for IHC tests are preserved in 10% formalin. In this study, nine formalin-fixed pathological samples from three goats suspected of PPR were processed for extraction of PPR viral RNA and analyzed for detection with real-time reverse transcription-polymerase chain reaction (qRT-PCR) assay. The results showed that five out of the nine tested samples returned positive for presences PPR viral genome. This study has established that field pathological samples of PPR-suspected cases, collected and stored in 10% formalin for up 2 years, could be used for PPR virus RNA extraction for disease virus confirmation.

Chanzu, NM, Mwanda W, Julius Oyugi, Anzala O.  2015.  Mucosal Blood Group Antigen Expression Profiles and HIV Infections: A Study among Female Sex Workers in Kenya., 2015. PloS one. 10(7):e0133049. Abstract

The ABO blood group antigens are carbohydrate moieties expressed on human red blood cells however; these antigens can also be expressed on some other cells particularly the surface of epithelial cells and may be found in mucosal secretions. In many human populations 80% secrete ABO antigens (termed 'secretors') while 20% do not (termed 'non-secretors'). Furthermore, there are disease conditions that are associated with secretor status.

Juno, JA, Stalker AT, Waruk JLM, Julius Oyugi, Kimani M, Plummer FA, Kimani J, Fowke KR.  2015.  Elevated expression of LAG-3, but not PD-1, is associated with impaired iNKT cytokine production during chronic HIV-1 infection and treatment., 2015. Retrovirology. 12:17. Abstract

LAG-3 is a potent negative regulator of the immune response but its impact in HIV infection in poorly understood. Unlike exhaustion markers such as PD-1, Tim-3, 2B4 and CD160, LAG-3 is poorly expressed on bulk and antigen-specific T cells during chronic HIV infection and its expression on innate lymphocyte subsets is not well understood. The aim of this study was to assess LAG-3 expression and association with cellular dysfunction on T cells, NK cells and iNKT cells among a cohort of healthy and HIV-infected female sex workers in Nairobi, Kenya.

Erick Kipkoech Rutto, Joshua Nyagol, Julius Oyugi, Samson Ndege, Noel Onyango, Obala A, Chrispinus J Simiyu, Gye Boor, Winfrida Chelangat Cheriro, Otsyula B, Estambale B.  2015.  Effects of HIV-1 infection on malaria parasitemia in milo sub-location, western Kenya., 2015. BMC research notes. 8:303. Abstract

Malaria and HIV infections are both highly prevalent in sub-Saharan Africa, with HIV-infected patients being at higher risk of acquiring malaria. HIV-1 infection is known to impair the immune response and may increase the incidence of clinical malaria. However, a positive association between HIV-1 and malaria parasitaemia is still evolving. Equally, the effect of malaria on HIV-1 disease stage has not been well established, but when fever and parasitemia are high, malaria may be associated with transient increases in HIV-1 viral load, and progression of HIV-1 asymptomatic disease phase to AIDS.

Waruk, JLM, Machuki Z, Mesa C, Juno JA, Anzala O, Sharma M, Ball BT, Julius Oyugi, Kiazyk S.  2015.  Cytokine and chemokine expression profiles in response to Mycobacterium tuberculosis stimulation are altered in HIV-infected compared to HIV-uninfected subjects with active tuberculosis., 2015 Sep. Tuberculosis (Edinburgh, Scotland). 95(5):555-61. Abstract

Mycobacterium tuberculosis (Mtb) infects nearly 2 million people annually and is the most common cause of death in HIV-infected individuals. Tuberculosis (TB) diagnostics cater to HIV-uninfected individuals in non-endemic countries, are expensive, slow, and lack sensitivity for those most affected. Patterns of soluble immune markers from Mtb-stimulated immune cells are not well defined in HIV co-infection. We assessed immune differences between HIV-infected and HIV-uninfected individuals with active TB utilizing IFNγ-based QuantiFERON®-TB Gold In-Tube (QFT) testing in Nairobi, Kenya. Excess QFT supernatants were used to measure cytokine and chemokine responses by a 17-plex bead array. Mtb/HIV co-infected participants were significantly less likely to be QFT+ (47.2% versus 84.2% in the HIV-uninfected group), and demonstrated lower expression of all cytokines except for IFNα2. Receiver operator characteristic analyses identified IL-1α as a potential marker of co-infection. Among HIV-infected individuals, CD4+ T cell count correlated weakly with the expression of several analytes. Co-expression analysis highlighted differences in immune profiles between the groups. These data suggest that there is a unique and detectable Mtb-specific immune response in co-infection. A better understanding of Mtb immunology can translate into much needed immunodiagnostics with enhanced sensitivity in HIV-infected individuals, facilitating their opportunity to obtain live-saving treatment.

2014

Maina, AN, Mwaura FB, Julius Oyugi, Goulding D, Toribio AL, Kariuki S.  2014.  Characterization of Vibrio cholerae bacteriophages isolated from the environmental waters of the Lake Victoria region of Kenya., 2014 Jan. Current microbiology. 68(1):64-70. Abstract

Over the last decade, cholera outbreaks have become common in some parts of Kenya. The most recent cholera outbreak occurred in Coastal and Lake Victoria region during January 2009 and May 2010, where a total of 11,769 cases and 274 deaths were reported by the Ministry of Public Health and Sanitation. The objective of this study is to isolate Vibrio cholerae bacteriophages from the environmental waters of the Lake Victoria region of Kenya with potential for use as a biocontrol for cholera outbreaks. Water samples from wells, ponds, sewage effluent, boreholes, rivers, and lakes of the Lake Victoria region of Kenya were enriched for 48 h at 37 °C in broth containing a an environmental strain of V. cholerae. Bacteriophages were isolated from 5 out of the 42 environmental water samples taken. Isolated phages produced tiny, round, and clear plaques suggesting that these phages were lytic to V. cholerae. Transmission electron microscope examination revealed that all the nine phages belonged to the family Myoviridae, with typical icosahedral heads, long contractile tails, and fibers. Head had an average diameter of 88.3 nm and tail of length and width 84.9 and 16.1 nm, respectively. Vibriophages isolated from the Lake Victoria region of Kenya have been characterized and the isolated phages may have a potential to be used as antibacterial agents to control pathogenic V. cholerae bacteria in water reservoirs.

Dundon, WG, Kihu SM, Settypalli BTK, Gitao GC, Bebora LC, John NM, Oyugi JO, Silber R, Loitsch A, Diallo A.  2014.  First Complete Genome Sequence of a Lineage III Peste des Petits Ruminants Virus., 2014. Genome announcements. 2(5) Abstract

We report the first complete genome sequence of a lineage III peste des petits ruminants virus (KN5/2011) using RNA extracted from goat lung tissue collected in Kenya in 2011. The genome shows the highest nucleotide sequence identity with lineage II peste des petits ruminants viruses (PPRVs) (86.1 to 87.2%) and the lowest with lineage IV PPRVs (82.5 to 83.8%).

Juno, JA, Lajoie J, Stalker AT, Julius Oyugi, Kimani M, Kimani J, Plummer FA, Fowke KR.  2014.  Enrichment of LAG-3, but not PD-1, on double negative T cells at the female genital tract., 2014 Dec. American journal of reproductive immunology (New York, N.Y. : 1989). 72(6):534-40. Abstract

The expression of inhibitory markers such as LAG-3 and PD-1 on T lymphocytes regulates immune function. Their expression at the genital mucosa is poorly understood, but regulation of immune activation at the female genital tract likely controls susceptibility to sexually transmitted infections.

2013

Milugo, TK, Omosa LK, Ochanda JO, Owuor BO, Wamunyokoli FA, Oyugi JO, Ochieng JW.  2013.  Antagonistic effect of alkaloids and saponins on bioactivity in the quinine tree (Rauvolfia caffra sond.): further evidence to support biotechnology in traditional medicinal plants., 2013. BMC complementary and alternative medicine. 13:285. Abstract

The Quinine tree (Rauvolfia caffra) is used as a medicinal plant among traditional communities in many countries to manage tumors and other diseases associated with oxidative stress. To validate indigenous knowledge and possibly position this herb for technology uptake and utilization, we established the level of antioxidant activity in R. caffra, and probed for the presence of associated phytochemicals.

2012

Choi, RY, Fowke KR, Juno J, Lohman-Payne B, Oyugi JO, Brown ER, Bosire R, John-Stewart G, Farquhar C.  2012.  C868T single nucleotide polymorphism and HIV type 1 disease progression among postpartum women in Kenya., 2012 Jun. AIDS research and human retroviruses. 28(6):566-70. Abstract

The C868T single nucleotide polymorphism in the CD4 receptor encodes an amino acid substitution of tryptophan for arginine in the third domain. Previous studies suggest that C868T increases the risk of HIV-1 acquisition; however, the influence of this single nucleotide polymorphism (SNP) on disease progression has not been established. The presence of the C868T polymorphism was not statistically significantly associated with HIV-1 disease progression outcomes in a cohort of postpartum Kenyan women.

f c Francis M. Awahe, Peter N. Uzoegwua, PIJOJRO, XiaoJian Yaob, Frauke Fehrmannb KFMERO.  2012.  Free radical scavenging activity, phenolic contents and cytotoxicity of selected Nigerian medicinal plants. Food chemistry. 131(4):1279–1286.

2011

Borkow G, Covington CY, GAOJAMSBOJM.  2011.  Prevention of Human Immunodeficiency Virus Breastmilk Transmission with Copper Oxide: Proof-of-Concept Study. Breastfeed Med. :165-70.
Choi RY, Fowke KR, JL-POJOBERBJ-SFJBR.  2011.  C868T Single Nucleotide Polymorphism and HIV Type 1. Disease Progression among Postpartum Women in Kenya. AIDS Res Hum Retroviruses.
Thomas, TK; Masaba, BCB; NZMOJTMC; BSR; R; C.  2011.  Triple-antiretroviral prophylaxis to prevent mother-to-child HIV transmission through breastfeeding--the Kisumu Breastfeeding Study, Kenya: a clinical trial.. Abstract

Effective strategies are needed for the prevention of mother-to-child HIV transmission (PMTCT) in resource-limited settings. The Kisumu Breastfeeding Study was a single-arm open label trial conducted between July 2003 and February 2009. The overall aim was to investigate whether a maternal triple-antiretroviral regimen that was designed to maximally suppress viral load in late pregnancy and the first 6 mo of lactation was a safe, well-tolerated, and effective PMTCT intervention. METHODS AND FINDINGS: HIV-infected pregnant women took zidovudine, lamivudine, and either nevirapine or nelfinavir from 34-36 weeks' gestation to 6 mo post partum. Infants received single-dose nevirapine at birth. Women were advised to breastfeed exclusively and wean rapidly just before 6 mo. Using Kaplan-Meier methods we estimated HIV-transmission and death rates from delivery to 24 mo. We compared HIV-transmission rates among subgroups defined by maternal risk factors, including baseline CD4 cell count and viral load. Among 487 live-born, singleton, or first-born infants, cumulative HIV-transmission rates at birth, 6 weeks, and 6, 12, and 24 mo were 2.5%, 4.2%, 5.0%, 5.7%, and 7.0%, respectively. The 24-mo HIV-transmission rates stratified by baseline maternal CD4 cell count <500 and ≥500 cells/mm(3) were 8.4% (95% confidence interval [CI] 5.8%-12.0%) and 4.1% (1.8%-8.8%), respectively (p = 0.06); the corresponding rates stratified by baseline maternal viral load <10,000 and ≥10,000 copies/ml were 3.0% (1.1%-7.8%) and 8.7% (6.1%-12.3%), respectively (p = 0.01). None of the 12 maternal and 51 infant deaths (including two second-born infants) were attributed to antiretrovirals. The cumulative HIV-transmission or death rate at 24 mo was 15.7% (95% CI 12.7%-19.4%). CONCLUSIONS: This trial shows that a maternal triple-antiretroviral regimen from late pregnancy through 6 months of breastfeeding for PMTCT is safe and feasible in a resource-limited setting. These findings are consistent with those from other trials using maternal triple-antiretroviral regimens during breastfeeding in comparable settings.

Thomas, TK, Masaba R, Borkowf CB, Ndivo R, Zeh C, Misore A, Otieno J, Jamieson D, Thigpen MC, Bulterys M, Slutsker L, De Cock KM, Amornkul PN, Greenberg AE, Fowler MG, Team KBSS, Mbori-Ngacha DA, et al.  2011.  http://erepository.uonbi.ac.ke/handle/123456789/30836. Abstract

Effective strategies are needed for the prevention of mother-to-child HIV transmission (PMTCT) in resource-limited settings. The Kisumu Breastfeeding Study was a single-arm open label trial conducted between July 2003 and February 2009. The overall aim was to investigate whether a maternal triple-antiretroviral regimen that was designed to maximally suppress viral load in late pregnancy and the first 6 mo of lactation was a safe, well-tolerated, and effective PMTCT intervention. METHODS AND FINDINGS: HIV-infected pregnant women took zidovudine, lamivudine, and either nevirapine or nelfinavir from 34-36 weeks' gestation to 6 mo post partum. Infants received single-dose nevirapine at birth. Women were advised to breastfeed exclusively and wean rapidly just before 6 mo. Using Kaplan-Meier methods we estimated HIV-transmission and death rates from delivery to 24 mo. We compared HIV-transmission rates among subgroups defined by maternal risk factors, including baseline CD4 cell count and viral load. Among 487 live-born, singleton, or first-born infants, cumulative HIV-transmission rates at birth, 6 weeks, and 6, 12, and 24 mo were 2.5%, 4.2%, 5.0%, 5.7%, and 7.0%, respectively. The 24-mo HIV-transmission rates stratified by baseline maternal CD4 cell count <500 and ≥500 cells/mm(3) were 8.4% (95% confidence interval [CI] 5.8%-12.0%) and 4.1% (1.8%-8.8%), respectively (p = 0.06); the corresponding rates stratified by baseline maternal viral load <10,000 and ≥10,000 copies/ml were 3.0% (1.1%-7.8%) and 8.7% (6.1%-12.3%), respectively (p = 0.01). None of the 12 maternal and 51 infant deaths (including two second-born infants) were attributed to antiretrovirals. The cumulative HIV-transmission or death rate at 24 mo was 15.7% (95% CI 12.7%-19.4%). CONCLUSIONS: This trial shows that a maternal triple-antiretroviral regimen from late pregnancy through 6 months of breastfeeding for PMTCT is safe and feasible in a resource-limited setting. These findings are consistent with those from other trials using maternal triple-antiretroviral regimens during breastfeeding in comparable settings.

1. Choi RY, Fowke KR, JL-POJOBERBJ-SFJBR.  2011.  C868T Single Nucleotide Polymorphism and HIV Type 1. Disease Progression Among Postpartum Women in Kenya. AIDS Res Hum Retroviruses. 2011 Sep 27.. AIDS Res Hum Retroviruses. Abstractsingle_nucleotide_polymorphism_and_hiv_type_1._disease_progression_among_postpartum_women_in_kenya.pdf

The C868T single nucleotide polymorphism in the CD4 receptor encodes an amino acid substitution of tryptophan for arginine in the third domain. Previous studies suggest that C868T increases the risk of HIV-1 acquisition; however, the influence of this single nucleotide polymorphism (SNP) on disease progression has not been established. The presence of the C868T polymorphism was not statistically significantly associated with HIV-1 disease progression outcomes in a cohort of postpartum Kenyan women.

Borkow G, Covington CY, GAOJAMSBOJM.  2011.  Prevention of Human Immunodeficiency Virus Breastmilk Transmission with Copper Oxide: Proof-of-Concept Study. Breastfeed Med. 2011 Aug; 6:165-70.. Breastfeed Med. Abstractprevention_of_human_immunodeficiency_virus_breastmilk_transmission_with_copper_oxide.pdf

Abstract
BACKGROUND: Human immunodeficiency virus type 1 (HIV-1) transmission through breastmilk is the chief modality through which HIV-1 is transmitted from HIV-1-infected mothers to their babies in developing countries, where alternative feeding options lack practical feasibility. The development of an approach to inactivate the HIV-1 virions ingested by an infant on a daily basis through breastmilk is thus of critical importance.
METHODS:
Copper has potent virucidal properties. Stoichiometric concentrations of copper ions inactivate the HIV-1 protease, which is essential for viral replication. Cell-free and cell-associated HIV-1 infectivity is inhibited when the virus is exposed to copper oxide in a dose-dependent manner. Passage of high titers of a wide range of HIV-1 isolates, spiked in culture medium, through filters containing copper oxide powder resulted in their deactivation.
RESULTS:
In the current study, we demonstrate that the infectivity of three different HIV-1 isolates, spiked in breastmilk obtained from HIV-1-seronegative donors, or of wild-type isolates found in breastmilk obtained from HIV-1-seropositive donors, is drastically reduced (>98%) when exposed to copper oxide.
CONCLUSIONS:
This study is proof of concept that copper oxide is efficacious against HIV-1 found in breastmilk and serves as the basis for further research aimed at determining the possible effects that copper may have on the nutritional and anti-infective properties of breastmilk. Furthermore, this supports the continuing study of the feasibility of developing a filtering device, such as an "at-the-breast" disposable shield that can be used discreetly and safely by HIV-1-infected mothers during breastfeeding.

2010

Francis M. Awah, Peter N. Uzoegwu, JOJRPIO, Xiao-Jian Yao, Keith R. Fowke MEO.  2010.  Free radical scavenging activity and immunomodulatory effect of Stachytarpheta angustifolia leaf extract.. Food Chemistry. 119(4):1409-1416.
and 1. Francis M. Awah, Peter N. Uzoegwu, JOJRPIX-JYKFMOR.  2010.  Free radical scavenging activity and immunomodulatory effect of Stachytarpheta angustifolia leaf extract. Food Chemistry, Volume 119, Issue 4, 15 April 2010, Pages 1409-1416.. Food Chemistry. Abstract

Abstract
Plant extracts with antioxidant activity could also have immunomodulatory ability. The free radical scavenging activity of an ethanol extract of the leaves of Stachytarpheta angustifolia was assessed by measuring its capability for scavenging 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical, superoxide anion radical (O2-), hydroxyl radical (OH), nitric oxide radicals (NO), as well as its ability to inhibit lipid peroxidation, using appropriate assay systems. The extract was also assessed for its ability to decrease the phenotypic expression of the immune activation markers CD38 and CD69. This extract showed a potent antioxidant activity in the DPPH radical-scavenging assay (EC50 = 9.65 μg/ml), significantly inhibited OH radical (IC50 = 99.43 μg/ml), O2- anion radical (IC50 = 64.68 μg/ml), non-enzymatic lipid peroxidation (IC50 = 282.91 μg/ml) and accumulation of nitrite in vitro. Ex vivo the extract inhibited phorbol myristate acetate (PMA)-induced production of superoxide anion (O2-), and also exhibited a dose-dependent reduction in the levels of the immune activation marker CD38 and CD69 on phytohemagglutinin A (PHA)-stimulated human peripheral blood mononuclear cells (PBMC). The observed antioxidant activity and immunomodulatory potentials of the extract suggest that it could impart health benefits when consumed. However, further investigation to verify its effect in vivo is warranted.

2009

1. Oyugi JO, Vouriot FC, AWLLAMAYSRPELJSJNBTBJJSM.  2009.  A Common CD4 Gene Variant Is Associated with an Increased Risk of HIV-1 Infection in Kenyan Female Commercial Sex Workers. J Infect Dis. 2009 May 1;199 (9):1327-1334.. J Infect Dis. Abstracta_common_cd4_gene_variant_is_associated_with_an_increased_risk_of_hiv-1_infection_in_kenyan_female_commercial_sex_workers._j.pdf

Abstract
BACKGROUND:
It has been predicted that CD4 C868T, a novel CD4 single-nucleotide polymorphism (SNP) that has been found to be highly prevalent among Africans, changes the tertiary structure of CD4, which may alter susceptibility to human immunodeficiency virus (HIV) infection.
METHODS:
Participants were from a Kenyan cohort and included 87 uninfected and 277 HIV-1-infected individuals. DNA sequencing was used to determine CD4 genotype. A2.01 cells expressing similar levels of either wild-type CD4 or CD4-Trp240 as well as peripheral blood mononuclear cells from uninfected donors were infected with HIV-1(IIIB) or a Kenyan primary HIV-1 isolate. HIV-1 p24 enzyme-linked immunosorbent assay was used to determine the outcome of infection.
RESULTS:
CD4 C868T was found to be significantly more prevalent among HIV-1-infected participants than among HIV-1-uninfected participants (P = .002), and C868T was associated with an increased incidence of HIV-1 infection as well (P = .005, log-rank test; P = .009, Wilcoxon test), with an odds ratio of 2.49 (P = .009). Both in vitro and ex vivo models demonstrated a significant association between CD4 C868T and susceptibility to HIV-1 infection (P < .001 and P = .003, respectively).
CONCLUSION:
Overall, the present study found a strong correlation between CD4 C868T and increased susceptibility to HIV-1 infection. Given the high prevalence of both HIV infection and CD4 C868T in African populations, the effect of this SNP on the epidemic in Africa could be dramatic

1. Julius Oyugi, Fredrick Oyugi, COWJJBOA.  2009.  Use of serologic testing algorithm for recent HIV seroconversion(STARHS) to estimate HIV-1 incidence among adults visiting a Kenyan tertiary health institution. East African Medical Journal volume 86, no. 5; 2009.. . East African Medical Journal volume 86. Abstractuse_of_serologic_testing_algorithm_for_recent_hiv_seroconversionstarhs_to_estimate_hiv-1_incidence_among_adults_visiting_a_kenyan_tertiary_health_institution._.pdf

Abstract
OBJECTIVE:
To determine HIV high risk groups among adults visiting Kenyatta National Hospital Voluntary Counselling and Testing Centre by use of Serologic Testing Algorithm for Recent HIV Seroconversion (STARHS).
DESIGN:
A cross-sectional study of adults.
SETTING:
Kenyatta National Hospital Voluntary and Counselling Centre.
RESULTS:
Of the 6,415 adults screened for antibodies to HIV at Kenyatta National Hospital VCT Centre between July 2002 and February 2003, 728 tested positive in the two HIV screening tests used at the center, indicating a prevalence of 11%. Of these seropositive cases, 355 consented to participate in the study. Using STARHS, 34 (9.6%) of the plasma samples were classified as being from individuals with recent infection (within 170 days), giving an annual estimated HIV-1 incidence in this population of 1.3 infections per 100 person-years with a 95% CI of 0.872-1.728%. Young adults had a higher rate of new infection than older adults. Young females were infected much earlier in life, with a peak age of new infections of 26 years, versus 31 years for young males.
CONCLUSION:
This study confirms our hypothesis that STARHS or Detuned assay can be used to determine HIV incidence in this population. The HIV high risk groups as identified by this study are young women between ages 16 to 26 years old and men between ages 45 to 55 years of age.

2007

warming and the emergence of ancient pathogens in arctic, GC’s.  2007.  Oyugi JO, Hongyu Qiu and David Safronetz. Medical Hypotheses .

2005

1. Oyugi J. Judie Alimonti, Francoise Vouriot, SWFPJBKFA.  2005.  The role of CD4 polymorphism on HIV-1 infection. , June 9th. 2005. Canadian Student Health Research Days, . , Canada

2004

1. Farquhar C, Rowland-Jones S, M-NRLSOOROODMBJ.  2004.  Human leukocyte antigen (HLA) B*18 and protection against mother- to-child HIV type1 transmission. AIDS Res Hum Retro . Abstract

Abstract
Human leukocyte antigen (HLA) molecules regulate the cellular immune system and may be determinants of infant susceptibility to human immunodeficiency virus type 1 (HIV-1) infection. Molecular HLA typing for class I alleles was performed on infants followed in a Kenyan perinatal cohort. Early HIV-1 infection status was defined as infection occurring at birth or month 1, while late infection via breast milk was defined as first detection of HIV-1 after 1 month of age. Likelihood ratio tests based on a proportional hazards model adjusting for maternal CD4 T cell count and HIV-1 viral load at 32 weeks of gestation were used to test associations between infant allelic variation and incident HIV-1 infection. Among 433 infants, 76 (18%) were HIV-1 infected during 12 months of follow-up. HLA B*18 was associated with a significantly lower risk of early HIV-1 transmission [relative risk (RR) = 0.26; 95% confidence interval (CI) 0.04–0.82], and none of the 24 breastfeeding infants expressing HLA B*18 who were uninfected at month 1 acquired HIV-1 late via breast milk. We observed a trend toward increased early HIV-1 acquisition for infants presenting HLA A*29 (RR = 2.0; 95% CI 1.0–3.8) and increased late HIV-1 acquisition via breast milk for both Cw*07 and Cw*08 (RR = 4.0; 95% CI 1.0–17.8 and RR = 7.2; 95% CI 1.2–37.3, respectively). HLA B*18 may protect breast-feeding infants against both early and late HIV-1 acquisition, a finding that could have implications for the design and monitoring of HIV-1 vaccines targeting cellular immune responses against HIV-1.

1. Fang G, Kuiken C, WR-JPCCHKAAOBKPSMKBSF.  2004.  Long-term survivors in Nairobi: complete HIV-1 RNA sequences and immunogenetic associations. J Infect Dis. Abstractlong_term_survivors_in_nairobi_complete_hiv_1_rna_sequences_and_immunogenetic_associations.pdf

Abstract To investigate African long-termsurvivors (LTSs) infected with non-subtype B human immunodeficiency virus type 1 (HIV- 1), we obtained full-length HIV-1 RNA sequences and immunogenetic profiles from 6 untreated women enrolled in the Pumwani Sex Worker Cohort in Nairobi, Kenya. There were no discernible sequence changes likely to cause attenuation. CCR2-V64I, an immunogenetic polymorphism linked to LTSs, was detected in 4 women, all of whom carried the HLA B58 allele. Further investigation of 99 HIV-1-infected Nairobi women found an association between CCR2-V64I and HLA B58 (P = .0048). Studying the interaction among immunogenetics, immune responses, and viral sequences from all HIV- 1 subtypes may increase our understanding of slow HIV-1 disease progression. Sub-Saharan Africa accounts for 70% of HIV-1-infected individuals globally, and infected women in this region outnumber men. The study of long-term survivors (LTSs) is relevant to pathogenesis and the design of an HIV-1 vaccine. The HIV- 1 subtypes and host immunogenetics of LTSs in Africa differ from those of most LTSs studied previously [6–6]; for example, the HLA types are more diverse [6], and Δ32 mutations in coreceptor CCR5 are rarely seen [4]. Recombination between different HIV-1 subtypes has been well documented [2, 3, 7] and, along with viral diversity, is also relevant to the design of a vaccine. Analysis of both viral diversity and intersubtype recombination would benefit from the sequencing of entire viral genomes derived from plasma virions. The examination of plasma HIV-1 RNA offers an opportunity to observe the replicating virus population, including recombinant genomes in circulating viral particles. Nairobi sex workers, who are exposed to a range of viral strains, may be infected with intersubtype recombinants. To investigate pathogenesis in women with non-clade B HIV-1 infection, we analyzed complete HIV-1 RNA sequences, immunogenetic traits, immune responses, coreceptor utilization, and drug resistance in untreated LTSs from Kenya. Subjects and methods. The subjects were untreated HIV- 1-infected adult women enrolled in the Pumwani Sex Worker Cohort in Nairobi, Kenya [1]. The research was approved by the Kenyatta National Hospital National Ethical and Scientific Review Committee, the University of Manitoba Use of Human Subjects in Research Committee, and the New York State Department of Health Institutional Review Board. Within this cohort, long-term nonprogressors (LTNPs) and LTSs were identified [1]. Both LTSs and LTNPs had been infected with HIV-1 for ⩾10 years, and LTNPs had maintained CD4+ T cell counts ⩾500 cells/μL. To detect coreceptor polymorphisms, human genotyping was performed as
described elsewhere [4, 8]. Extraction of viral RNA from plasma, reverse transcription, long polymerase chain reaction (PCR) amplification, and analysis of full-length HIV-1 sequences were performed as described elsewhere [7]. Phylogenetic trees were constructed, and HIV-1 subtypes and recombinants were determined as described elsewhere [7]. Full-length HIV-1 env genes were cloned from plasma, and coreceptor usage was determined phenotypically by the use of GHOST cells [9]. The V3 loop sequence of env clones was also determined and was used to genotypically predict coreceptor utilization [10]. Molecular class I HLA types were determined as described elsewhere [6]. Neutralizing antibodies were detected as described elsewhere [11]. Genotypic resistance to antiretroviral agents was analyzed by the ADRA program [2]; phenotypic resistance was measured by the PhenoSense assay [12]. Several nonparametric tests of association were used to correlate the immunogenetic data with the virologic and clinical data. A 2-sided Wilcoxon rank sum test was used to test differences between continuous measures such as the number of CD4+ T cells and viral load. Fisher's exact test was used to analyze HLA types and coreceptor polymorphisms. A number of genetic analyses were performed by use of the Mendel statistical package [13]. Hardy-Weinberg-equilibrium (HWE) testing was used to examine whether the genotype frequencies for single loci were equal to products of the population allele frequencies. Gamete-phase equilibrium testing, a generalization of linkage-equilibrium testing that allows one to consider loci on different chromosomes, would normally be used to examine whether the joint frequencies of different alleles at several loci derived from the same parent are the product of the underlying population allele frequencies. To test gamete-phase equilibrium (or linkage equilibrium), however, knowledge of the parental source of the alleles at a locus (i.e., phase information) is required. Because phase information was unavailable but multilocus genotypes were known, we instead tested for genetic equilibrium. Genetic equilibrium holds only when both HWE and gamete-phase equilibrium are maintained. If genetic equilibrium was violated but separate tests of HWE were not rejected at all loci, then we assumed that genetic disequilibrium was a result of gamete-phase disequilibrium. Results. Table 1 shows the clinical, virologic, immunologic, and immunogenetic characteristics of 6 subjects in the Nairobi female sex-worker cohort who had been infected with nonsubtype B HIV-1 for ⩾10 years. Virions were isolated from plasma obtained from all 6 subjects in 1997 and also from additional plasma obtained in 1986 from subject ML013. The complete RNA genome was reverse-transcribed, amplified by long PCR, and directly sequenced. View larger version: In this page
In a new window Download as PowerPoint Slide Table 1. Virologic and immunogenetic characteristics in 6 untreated women in the Pumwani Sex Worker Cohort in Nairobi, Kenya. Complete HIV-1 RNA sequences were assembled, aligned, and analyzed by computational methods [7]. GenBank accession numbers are shown in table 1. Three subjects—ML752, ML013, and ML605—were infected with HIV-1 genomes identified as entirely subtype A; both the 1986 and the 1997 samples from ML013 also displayed subtype A genomes. Subject ML415 was infected with a viral genome identified as entirely subtype D. Two subjects displayed HIV-1 genomes that were intersubtype recombinants. Virus from ML672 was composed predominantly of clade A sequences with a clade C fragment in the pol gene. Subject ML249's recombinant virus was predominantly composed of clade D but also displayed a clade C fragment in nef and the 3' long terminal repeat. Sequences were examined for mutations that might contribute to attenuation of HIV-1. It is possible that single-nucleotide changes might help to attenuate the virus, and it was reported recently that R77Q, a mutation in the HIV-1 vpr gene, is associated with both LTNP infection and impaired induction of apoptosis [14]. This mutation was present in 3 of the 6 women studied, including 2 of the LTNPs (table 1); the association, however, was not statistically significant. No other clearly attenuating mutations or deletions were detected, nor any polymorphisms common to more than 1 sequence. We determined human genotypes for HIV-1 coreceptors, coreceptor-associated genes, and HLA class I haplotypes, to examine the contribution of immunogenetics to LTSs (table 1). All 6 subjects had homozygous wild-type CCR5 genotypes. Four subjects exhibited polymorphisms in the CCR2 gene; 2 LTNPs (ML672 and ML752) were homozygous for the V64I mutation, and 2 LTS subjects (ML013 and ML605) were heterozygous for it. It is noteworthy that all 4 women who carried the V64I allele also displayed the B58 HLA haplotype. Statistical analyses showed an association between the presence of the CCR2-V64I mutation (in at least 1 allele) and HLA type B58 (P=.06). To explore this association further, we expanded our immunogenetic analysis to include a larger group of 167 women in the Nairobi sex-worker cohort [1]. In addition to CCR2 and HLA B58, we examined the SDF-1α-3' untranslated region, bringing the total to 3 human genes, each located on a different chromosome [4]. There was no significant association between the CCR2 mutation and the SDF mutation. As shown in table 2, 99 (59.3%) of the 167 women were HIV-1 seropositive and 68 (40.7%) were HIV-1 seronegative. The B58 allele was of interest; all other alleles were combined, and the locus was treated as biallelic. No significant deviations from HWE were found for either CCR2 or HLA-B, either in the entire sample of 167 women or in the groups
stratified by HIV serostatus. In contrast, we did find, in the entire sample, significant evidence for gamete-phase disequilibrium between CCR2 and HLA B (P=.00780), indicating a highly significant association between CCR2-V64I and HLA type B58. This association was also significant in the HIV-seropositive subjects (P=.00486), but not in the HIV-seronegative subjects. View larger version: In this page In a new window Download as PowerPoint Slide Table 2. CCR2 mutations and HLA B58 in 167 Kenyan women in the Pumwani Sex Worker Cohort in Nairobi, Kenya. We determined CCR5-promoter genotypes (table 1). One LTNP (ML415) and one LTS (ML249) were homozygous for CCR5-59029G, a polymorphism associated with delayed progression of HIV-1 disease [4]. Coreceptor usage was determined for HIV-1 envelope clones obtained from 5 subjects (table 1). The majority (71/77 [92.2%]) of clones utilized CCR5. A minority of CXCR4-utilizing species were also detected in 3 subjects (ML672, ML752, and ML605). No significant drug-resistance mutations were seen. The Pheno- Sense assay was used to examine phenotypic resistance; only a specimen from subject ML415 gave a result, and no resistance was found. Although the absence of viable cells precluded functional studies of CTL activity, we were able to predict, on the basis of the donor HLA haplotype and predicted epitopes found in the immunology databases in the Los Alamos National Laboratory and Oxford University, the likely sites of CTL recognition. At least half the predicted epitopes carried 1 or more amino acid changes from the consensus sequence (data not shown); however, KAFSPEVIPMF, the immunodominant target of CTL recognition through HLA-B57 and B58 in HIV-1 gag, was conserved in all donors [15]. Neutralizing antibody titers ranged from negative to 1:640 (table 1). The serum demonstrated neutralization against strain MN (clade B) but not against strain 92/UG/31 (clade A). Discussion. This study is one of the first to characterize female LTSs and LTNPs from Africa, where both HIV-1 subtypes and immunogenetic traits differ from those of LTSs studied previously. One of the remarkable features of these LTSs is their fairly high viral loads (table 1).
These Kenyan subjects managed to survive, most of them as asymptomatics, for periods of 12–16 years, without antiretroviral treatment. Computational analyses of the complete HIV-1 RNA sequences confirmed both the frequency of intersubtype recombination and the particular HIV-1 subtypes observed in a recent study from Kenya [3]. One LTNP (ML672) and 1 LTS (ML249) had recombinant genomes. The sequence data, which are derived from plasma virions, provide direct evidence of recombinant genomes in circulating viral particles. Computational analyses of the sequences did not reveal any clearly attenuating mutations except for the vpr R77Q mutation (table 1) [14]; in our small study, the association between this mutation and LTSs was suggestive but not significant. All of the sequences analyzed in this study appeared to be intact and gave no indication that they coded for nonfunctional proteins. In fact, when multiple viral env genes from these subjects were cloned into an expression system to determine coreceptor utilization, most clones yielded functional envelopes. Although it is possible that 1 or more point mutations in the viral genomes may have diminished the pathogenicity of the viruses infecting these 6 women, we did not identify any deletions or mutations that would clearly confer attenuation on any of the viruses. Immunogenetics may have contributed to LTS status in this study (table 1). CCR2-V64I, previously linked to LTSs, was detected in 4 women. A highly significant correlation between the presence of the CCR2-V64I mutation and the HLA B58 allele was found in 167 women in the Nairobi cohort. The association was particularly strong in the 99 women who were HIV-1 seropositive, although it was not significant in the 68 women who were HIV-1 seronegative. The stronger association between these 2 alleles in the infected women, compared with that in the uninfected women, may reflect, in this group, a selection for LTSs bearing both V64I and B58 genes. An alternative explanation, however, is possible, reflecting the genetics of the population under study: when 2 loci are close to each other on a chromosome, departure from gamete-phase equilibrium is often taken as evidence for linkage disequilibrium; because CCR2 and HLA B genes are on different chromosomes, departure fromgenetic equilibrium is likely due to recent ethnic admixture in these subjects; however, joint selective pressures may also be acting on the 2 genes. The association of these human genes, CCR2 and HLA B58, has not been previously noted, and it may possibly provide a clue to the manner in which CCR2 affects the pace of HIV-1 infection. Although multiple studies, including 1 focusing on the Nairobi cohort [5], have reported that the CCR2-V64I allele may slow the progression of HIV-1 disease, the mechanism by which the mutation acts is still unclear [4, 5]. The HLA B57 allele, which is related to B58, has also been associated with both slowed progression of disease and long-term survival [6, 15]. The close association, in HIV-1-infected women, between the CCR2 mutation and B58 suggests that the V64I allele may affect the pace of HIV-1 infection in part or entirely through the HLA B58 haplotype. This question necessitates further investigation. Finally, these studies suggest that
studying the interaction among immunogenetics, immune responses, and viral sequences from all HIV-1 subtypes may increase our understanding of the slow progression of HIV-1 disease.

2001

Owino, AO, Oyugi JO, Nasirwa OO, Bennun LA.  2001.  Patterns of variation in waterbird numbers on four Rift Valley lakes in Kenya, 1991–1999. Abstract

Waterbird populations were censused each January from 1991 to 1999 at Lakes Naivasha, Elmenteita and Nakuru and from 1992 at Lake Bogoria. These shallow lakes in the Kenyan Rift Valley fluctuate greatly in water level and alkalinity. All but Naivasha are usually saline; Nakuru and Elmenteita at times support fish, while Bogoria is fishless. A standardized logarithmic index of relative abundance (value 1.0 for the mean) was calculated for each major waterbird group at each lake, and for Naivasha, Elmenteita and Nakuru combined (‘combined lakes’). Its variance was used to compare levels of variation within and across lakes. For the combined lakes, there was high variance in large piscivores (whether combined or separated into groups), grebes, rallids and flamingos. There was low variance in Palaearctic waders (combined or separated into groups), ibises and spoonbills and birds of prey. However, the lakes generally showed idiosyncratic patterns of variation across the different groups. Variance in the indices for birds of prey and kingfishers were consistently low (max. 0.036 and 0.042, respectively), but no group had consistently high variance across all sites. The variance for all birds (other than flamingos) combined was low (0.018 – 0.085) and similar across all lakes and for combined lakes (0.018). For the combined lakes, the variance for flamingos was five times higher than for all other birds (p<0.05), though the two variances were almost equal for Bogoria. Flamingos were the most variable at Naivasha (variance 0.281) followed by Elmenteita (0.177), Nakuru (0.101) and Bogoria (0.024, and significantly lower than all the rest, p<0.05). This was opposite in order to the mean numbers of flamingos recorded at each site. Large piscivores were relatively stable at Naivasha (variance 0.005) but much more variable at Elmenteita (0.199) and Nakuru (0.269). Patterns of variation within lakes were correlated for some groups, such as waders at Naivasha and large piscivores at Nakuru. These correlations could be related to local ecological conditions. However, there were few large correlations across sites, and these were mainly direct. There was, therefore, no evidence that a fixed population of waterbirds was distributing itself across sites according to conditions. Each lake thus seems to represent and independent entity, while the waterbirds they host evidently move much more widely afield than this portion of the Rift Valley.

1. MacDonald KS, Matukas L, EJEFKNNJOKKLMAR-JKJJ.  2001.  Human leucocyte antigen supertypes and immune susceptibility to HIV-1, implications for vaccine design.. Immunol Lett.. Abstracthuman_leucocyte_antigen_supertypes_and_immune_susceptibility_to_hiv-1_implications_for_vaccine_design._immunol_lett._.pdf

Abstract
T cell responses against HIV-1 have been identified in a number of exposed uninfected populations. We hypothesized that the ability to mount an effective T cell response is partly determined by the human leucocyte antigens (HLA) phenotype of the individual. We examined whether certain HLA supertypes were associated with differential HIV-1 susceptibility in sexually exposed adults and in the setting of mother to child HIV-1 transmission. By multivariate analysis, decreased HIV-1 infection risk was strongly associated with possession of a cluster of closely related class I HLA alleles (A2/6802 supertype) in sexually exposed adults (Hazard ratio=0.42, 95% confidence intervals (CI): 0.22-0.81, P=0.009) and perinatally exposed infants (Odds ratio=0.12, 95% CI: 0.03-0.54, P=0.006). The alleles in this HLA supertype are known in some cases, to present the same peptide epitopes (termed 'supertopes'), for T cell recognition. The identification of HIV-1 supertopes, which are associated with protection from HIV-1 infection, has important implications for the application of epitope-based HIV-l vaccines in a variety of racial groups.

wangi 1. Kaul R, Rowland-Jones SL, KFDKRNROOJKTP.  2001.  New insights into HIV-1specific cytotoxic T-lymphocyte responses in exposed, persistently seronegative Kenyan sex workers. Immunol Lett. . Abstractnew_insights_into_hiv-1specific_cytotoxic_t-lymphocyte_responses_in_exposed_persistently_seronegative_kenyan_sex_workers.pdf

Abstract
A clearer understanding of HIV-1 specific immune responses in highly-exposed, persistently seronegative (HEPS) subjects is important in developing models of HIV-1 protective immunity. HIV-1 specific cytotoxic T-lymphocytes (CTL) have been described in a cohort of HEPS Kenyan sex workers, and recent work has further elucidated these responses. CTL specific for HIV-1 Env were found in the blood of over half the sex workers meeting criteria for HIV resistance, and in some women recognized unmapped epitopes. The proportion of women with Env-specific CTL increased with the duration of uninfected HIV exposure, suggesting that these responses were acquired over time. CD8+ lymphocyte responses directed against predefined HIV-1 CTL epitopes from various HIV-1 genes were found in the blood and genital tract of >50% resistant sex workers, at a ten-fold lower frequency than in infected subjects. The epitope specificity of CD8+ responses differs between HEPS and HIV infected women, and in HEPS the maintenance of responses appears to be dependent on persistent HIV exposure. Several HIV-1 'resistant' sex workers have become HIV infected over the past 6 years, possibly related to waning of pre-existing HIV-specific CTL, and infection has often been associated with a switch in the epitope specificity of CD8+ responses. These findings suggest that vaccine-induced protective HIV immunity is a realistic goal, but that vaccine strategies of boosting or persistent antigen may be necessary for long-lived protection

2000

13. MacDonald KS, Fowke KR, KDVANNJBTBONGLKBRCWLJJE.  2000.  Influence of HLA supertypes on susceptibility and resistance to human immunodeficiency virus type 1 infection. J Infect Dis. Abstract

Abstract
Certain human leukocyte antigens, by presenting conserved immunogenic epitopes for T cell recognition, may, in part, account for the observed differences in human immunodeficiency virus type 1 (HIV-1) susceptibility. To determine whether HLA polymorphism influences HIV-1 susceptibility, a longitudinal cohort of highly HIV-1-exposed female sex workers based in Nairobi, Kenya, was prospectively analyzed. Decreased HIV-1 infection risk was strongly associated with possession of a cluster of closely related HLA alleles (A2/6802 supertype; incidence rate ratio [IRR], 0.45; 95% confidence interval [CI], 0.27-0.72; P=.0003). The alleles in this supertype are known in some cases to present the same peptide epitopes for T cell recognition. In addition, resistance to HIV-1 infection was independently associated with HLA DRB1*01 (IRR, 0.22; 95% CI, 0.06-0.60; P=.0003), which suggests that anti-HIV-1 class II restricted CD4 effector mechanisms may play an important role in protecting against viral challenge. These data provide further evidence that resistance to HIV-1 infection in this cohort of sex workers is immunologically mediated.

12. Fowke KR, Kaul R, RKLOKRWJNNJBTBBJJSJNSGMJJ.  2000.  HIV-1-specific cellular immune responses among HIV-1-resistant sex workers. Immunol Cell Biol. Abstract

Abstract
The goal of the present study was to determine whether there were HIV-1 specific cellular immune responses among a subgroup of women within a cohort of Nairobi prostitutes (n = 1800) who, despite their intense sexual exposure to HIV-1, are epidemiologically resistant to HIV-1 infection. Of the 80 women defined to be resistant, 24 were recruited for immunological evaluation. The HIV-1-specific T-helper responses were determined by IL-2 production following stimulation with HIV-1 envelope peptides and soluble gp120. Cytotoxic T lymphocyte responses were determined by lysis of autologous EBV-transformed B cell lines infected with control vaccinia virus or recombinant vaccinia viruses containing the HIV-1 structural genes env, gag and pol. Resistant women had significantly increased HIV-1 specific T-helper responses, as determined by in vitro IL-2 production to HIV-1 envelope peptides and soluble glycoprotein 120, compared with low-risk seronegative and HIV-1-infected controls (P < or = 0.01, Student's t-test). Seven of the 17 (41%) resistant women showed IL-2 stimulation indices > or = 2.0. HIV-1-specific CTL responses were detected among 15/22 (68.2%) resistant women compared with 0/12 low-risk controls (Chi-squared test, P < 0.001). In the two resistant individuals tested, the CTL activity was mediated by CD8+ effectors. Many HIV-1-resistant women show evidence of HIV-1-specific T-helper and cytotoxic responses. These data support the suggestion that HIV-1-specific T-cell responses contribute to protection against HIV-1 infection.

1999

14. Rowland-Jones SL, Dong T, DOHKKSAOMDKSLGPP.  1999.  Broadly cross-reactive HIV-specific cytotoxic T-lymphocytes in highly-exposed persistently seronegative donors. Immunol Lett. . Abstract

Abstract
HIV-specific cytotoxic T-lymphocytes (CTL) are believed to play a key part in the control of virus levels throughout HIV infection. An important goal of a potential prophylactic vaccine against HIV is therefore to elicit a strong CTL response which is broadly cross-reactive against a diverse range of HIV strains. We have detected HIV-specific CTL in two groups of highly-exposed but persistently seronegative female sex workers in Africa which show extensive cross-reactivity between different viral sequences. In a small group of women exposed to both HIV-1 and HIV-2 in Gambia, studied over 4 years, we have repeatedly detected HLA-B35-restricted CTL which exhibit cross-reactivity between the HIV-1 and HIV-2 sequences of the CTL epitopes. In women with particularly intense exposure to what are likely to be multiple clades of HIV-1 in Nairobi Kenya, we have detected CTL directed towards epitopes conserved between HIV-1 clades. In neither group is there any evidence that variation in CCR5 sequence or expression is responsible for their apparent resistance to HIV infection. However, in seropositive donors from Oxford infected with African strains of HIV-1, we have defined CTL responses which are specific for particular clades and have mapped some unique A clade CTL epitopes, together with others to highly-conserved regions of the virus. Further information about the extent of cross-reactive CTL immunity will be important for future vaccine design and evaluation.

1998

16. Rowland-Jones SL, Dong T, FKRKKNBAONBMDJPHT.  1998.  Cytotoxic T cell responses to multiple conserved HIV epitopes in HIV-resistant prostitutes in Nairobi. J Clin Invest. Abstract

Abstract
Many people who remain persistently seronegative despite frequent HIV exposure have HIV-specific immune responses. The study of these may provide information about mechanisms of natural protective immunity to HIV-1. We describe the specificity of cytotoxic T lymphocyte responses to HIV in seronegative prostitutes in Nairobi who are apparently resistant to HIV infection. These women have had frequent exposure to a range of African HIV-1 variants, primarily clades A, C, and D, for up to 12 yr without becoming infected. Nearly half of them have CTL directed towards epitopes previously defined for B clade virus, which are largely conserved in the A and D clade sequences. Stronger responses are frequently elicited using the A or D clade version of an epitope to stimulate CTL, suggesting that they were originally primed by exposure to these virus strains. CTL responses have been defined to novel epitopes presented by HLA class I molecules associated with resistance to infection in the cohort, HLA-A*6802 and HLA-B18. Estimates using a modified interferon-gamma Elispot assay indicate a circulating frequency of CTL to individual epitopes of between 1:3,200 and 1:50,000. Thus, HIV-specific immune responses-particularly cross-clade CTL activity- may be responsible for protection against persistent HIV infection in these African women.

15. Fowke KR, Dong T, R-JSLORWJKKBSJNSGMPFAJJP.  1998.  HIV type 1 resistance in Kenyan sex workers is not associated with altered cellular susceptibility to HIV type 1 infection or enhanced chemokine production. AIDS Res Hum Retroviruses. . Abstract

Abstract
A small group of women (n = 80) within the Nairobi-based Pumwani Sex Workers Cohort demonstrates epidemiologic resistance to HIV-1 infection. Chemokine receptor polymorphisms and beta-chemokine overproduction have been among the mechanisms suggested to be responsible for resistance to HIV-1 infection. This study attempts to determine if any of those mechanisms are protecting the HIV-1-resistant women. Genetic analysis of CCR5 and CCR3 from the resistant women demonstrated no polymorphisms associated with resistance. Expression levels of CCR5 among the resistant women were shown to be equivalent to that found in low-risk seronegative (negative) controls, while CXCR4 expression was greater among some of the resistant women. In vitro infection experiments showed that phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMCs) from resistant women were as susceptible to infection to T cell- and macrophage-tropic North American and Kenyan HIV-1 isolates as were the PBMCs from negative controls. No significant difference in circulating plasma levels of MIP-1alpha and MIP-1beta were found between the resistant women and negative or HIV-1-infected controls. In vitro cultures of media and PHA-stimulated PBMCs indicated that the resistant women produced significantly less MIP-1alpha and MIP-1beta than did negative controls and no significant difference in RANTES levels were observed. In contrast to studies in Caucasian cohorts, these data indicate that CCR5 polymorphisms, altered CCR5 and CXCR4 expression levels, cellular resistance to in vitro HIV-1 infection, and increased levels of beta-chemokine production do not account for the resistance to HIV-1 infection observed among the women of the Pumwani Sex Workers Cohort.

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