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Scientific Publications
Prevalence Incidence and Clearance of Anogenital Warts in Kenyan Men Reporting High Risk Sexual Behavior Including Men Who Have Sex With Men
Neme S, Wahome E, Mwashigadi G, Thiong'o AN, Stekler JD, Wald A, Sanders EJ, Graham SM
Prevalence, Incidence, and Clearance of Anogenital Warts in Kenyan Men Reporting High-Risk Sexual Behavior, Including Men Who Have Sex With Men. Open Forum Infect Dis 2015;2(2):ofv070 doi: 10.1093/ofid/ofv070
doi: 10.1093/ofid/ofv070
Abstract
Background. Human papillomavirus (HPV) causes a spectrum of disease, ranging from warts to cancer. Prevalence, incidence, and factors associated with anogenital warts in East African men are unknown. Methods. Kenyan men reporting high-risk sexual behavior were inspected for anogenital warts at enrollment and follow-up visits. Logistic regression was performed to identify associations with anogenital warts at baseline. Cox regression was performed to analyze predictors of incident anogenital warts, and Kaplan-Meier curves were used to estimate clearance. Results. Baseline anogenital wart prevalence in 1137 men was 2.9% (95% confidence interval [CI], 2.0%-4.0%) overall, 2.0% in human immunodeficiency virus (HIV)-uninfected men, and 9.4% in HIV-1-infected men (adjusted odds ratio, 5.43; 95% CI, 2.03-11.29). Over a median of 1.4 years, anogenital wart incidence among 1104 men was 5.3 (95% CI, 4.3-6.5) per 100 person-years. Having HIV-1 infection at baseline (adjusted hazard ratio [aHR], 1.66; 95% CI, 1.01-2.72) or a genital syndrome during follow-up (aHR, 4.78; 95% CI, 3.03-7.56) was associated with increased wart incidence. Wart clearance was lower in HIV-1-infected men (log-rank P<.001). Conclusions. Anogenital wart prevalence and incidence were increased in HIV-1-infected men, and anogenital warts co-occurred with other genital syndromes. Quadrivalent HPV vaccination should be recommended for young men in settings with high HIV-1 prevalence.
Scientific Publications
Identification of CD4 Binding Site Dependent Plasma Neutralizing Antibodies in an HIV 1 Infected Indian Individual
Khan L, Makhdoomi MA, Kumar S, Nair A, Andrabi R, Clark BE, Auyeung K, Bhattacharya J, Vajpayee M, Wig N, Pantophlet R, Luthra K
Identification of CD4-Binding Site Dependent Plasma Neutralizing Antibodies in an HIV-1 Infected Indian Individual. PLoS ONE 2015;10(5):e0125575 doi: 10.1371/journal.pone.0125575
Abstract
Dissecting antibody specificities in the plasma of HIV-1 infected individuals that develop broadly neutralizing antibodies (bNAbs) is likely to provide useful information for refining target epitopes for vaccine design. Several studies have reported CD4-binding site (CD4bs) antibodies as neutralization determinants in the plasma of subtype B-infected individuals; however there is little information on the prevalence of CD4bs specificities in HIV-infected individuals in India. Here, we report on the presence of CD4bs antibodies and their contribution to virus neutralization in the plasma from a cohort of HIV-1 infected Indian individuals. Plasma from 11 of the 140 HIV-1 infected individuals (7.9%) studied here exhibited cross-neutralization activity against a panel of subtype B and C viruses. Analyses of these 11 plasma samples for the presence of CD4bs antibodies using two CD4bs-selective probes (antigenically resurfaced HXB2gp120 core protein RSC3 and hyperglycosylated JRFLgp120 mutant ΔN2mCHO) revealed that five (AIIMS 617, 619, 627, 642, 660) contained RSC3-reactive plasma antibodies and only one (AIIMS 660) contained ΔN2mCHO-reactive antibodies. Plasma antibody depletion and competition experiments confirmed that the neutralizing activity in the AIIMS 660 plasma was dependent on CD4bs antibodies. To the best of our knowledge, this is the first study to report specifically on the presence of CD4bs antibodies in the plasma of a cohort of HIV-1 infected Indian donors. The identification of CD4bs dependent neutralizing antibodies in an HIV-1 infected Indian donor is a salient finding of this study and is supportive of ongoing efforts to induce similar antibodies by immunization.
Scientific Publications
A Phase I Double Blind Placebo Controlled Randomized Study of the Safety and Immunogenicity of an Adjuvanted HIV 1 Gag Pol Nef Fusion Protein and Adenovirus 35 Gag RT Int Nef Vaccine in Healthy HIV Uninfected African Adults
Omosa-Manyonyi G, Mpendo J, Ruzagira E, Kilembe W, Chomba E, Roman F, Bourguignon P, Koutsoukos M, Collard A, Voss G, Laufer D, Stevens G, Hayes P, Clark L, Cormier E, Dally L, Barin B, Ackland J, Syvertsen K, Zachariah D, Anas K, Sayeed E, Lombardo A, Gilmour J, Cox J, Fast P, Priddy F
A Phase I Double Blind, Placebo-Controlled, Randomized Study of the Safety and Immunogenicity of an Adjuvanted HIV-1 Gag-Pol-Nef Fusion Protein and Adenovirus 35 Gag-RT-Int-Nef Vaccine in Healthy HIV-Uninfected African Adults. PLoS ONE 2015;10(5):e0125954 doi: 10.1371/journal.pone.0125954
Abstract
Sequential prime-boost or co-administration of HIV vaccine candidates based on an adjuvanted clade B p24, RT, Nef, p17 fusion protein (F4/AS01) plus a non-replicating adenovirus 35 expressing clade A Gag, RT, Int and Nef (Ad35-GRIN) may lead to a unique immune profile, inducing both strong T-cell and antibody responses.
Scientific Publications
Incidence and predictors of attrition from antiretroviral care among adults in a rural HIV clinic in Coastal Kenya a retrospective cohort study
Hassan AS, Mwaringa SM, Ndirangu KK, Sanders EJ, de Wit TF, Berkley JA
Incidence and predictors of attrition from antiretroviral care among adults in a rural HIV clinic in Coastal Kenya: a retrospective cohort study. BMC Public Health 2015;15:478 doi: 10.1186/s12889-015-1814-2
Abstract
Scale up of antiretroviral therapy (ART) has led to substantial declines in HIV related morbidity and mortality. However, attrition from ART care remains a major public health concern and has been identified as one of the key reportable indicators in assessing the success of ART programs. This study describes the incidence and predictors of attrition among adults initiating ART in a rural HIV clinic in Coastal Kenya.
Scientific Publications
Understanding Adherence to Daily and Intermittent Regimens of Oral HIV Pre exposure Prophylaxis Among Men Who Have Sex with Men in Kenya
Mugo PM, Sanders EJ, Mutua G, van der Elst E, Anzala O, Barin B, Bangsberg DR, Priddy FH, Haberer JE
Understanding Adherence to Daily and Intermittent Regimens of Oral HIV Pre-exposure Prophylaxis Among Men Who Have Sex with Men in Kenya. AIDS Behav 2015;19(5):794-801 doi: 10.1007/s10461-014-0958-x
Abstract
A qualitative assessment of Kenyan men who have sex with men taking daily and intermittent oral HIV pre-exposure prophylaxis (PrEP) found stigma, sex work, mobility, and alcohol impacted adherence. We analyzed quantitative data from the same cohort to explore different definitions of intermittent adherence. Volunteers were randomized to daily emtricitabine/tenofovir or placebo, or intermittent (prescription: Mondays/Fridays/after sex, maximum 1 dose/day) emtricitabine/tenofovir or placebo (2:1:2:1), and followed for 4 months. By electronic monitoring, median adherence for daily dosing was 80 %. Median adherence for intermittent dosing was 71 % per a 'relaxed' definition (accounting for off-prescription dosing) and 40 % per a 'strict' definition (limited to the prescription). Factors associated with lower adherence included travel, transactional sex, and longer follow-up; higher adherence was associated with daily dosing and an income. The definition of intermittent dosing strongly affects interpretation of adherence. These findings suggest interventions should address challenges of mobility, sex work, and long-term PrEP.
Scientific Publications
Building the Human Vaccines Project strategic management recommendations and summary report of the 15 16 July 2014 business workshop
Schenkelberg T, Kieny MP, Bianco AE, Koff WC
Building the Human Vaccines Project: strategic management recommendations and summary report of the 15-16 July 2014 business workshop. Expert Rev Vaccines 2015;14(5):629-36 doi: 10.1586/14760584.2015.1013466
Abstract
The Human Vaccines Project is a bold new initiative, with the goal of solving the principal scientific problem impeding vaccine development for infectious diseases and cancers: the generation of specific, broad, potent and durable immune responses in humans. In the July 2014 workshop, 20 leaders from the public and private sectors came together to give input on strategic business issues for the creation of the Human Vaccines Project. Participants recommended the Project to be established as a nonprofit public-private partnership, structured as a global R&D consortium closely engaged with industrial partners, and located/affiliated with one or more major academic centers conducting vaccine R&D. If successful, participants concluded that the Project could greatly accelerate the development of new and improved vaccines, with the potential to transform disease prevention in the 21st century.
Scientific Publications
Emerging themes for sensitivity training modules of African healthcare workers attending to men who have sex with men a systematic review
Dijkstra M, van der Elst EM, Micheni M, Gichuru E, Musyoki H, Duby Z, Lange JM, Graham SM, Sanders EJ
Emerging themes for sensitivity training modules of African healthcare workers attending to men who have sex with men: a systematic review. Int Health 2015;7(3):151-62 doi: 10.1093/inthealth/ihu101
Abstract
Sensitivity training of front-line African health care workers (HCWs) attending to men who have sex with men (MSM) is actively promoted through national HIV prevention programming in Kenya. Over 970 Kenyan-based HCWs have completed an eight-modular online training free of charge (http://www.marps-africa.org) since its creation in 2011. Before updating these modules, we performed a systematic review of published literature of MSM studies conducted in sub-Saharan Africa (sSA) in the period 2011-2014, to investigate if recent studies provided: important new knowledge currently not addressed in existing online modules; contested information of existing module topics; or added depth to topics covered already. We used learning objectives of the eight existing modules to categorise data from the literature. If data could not be categorised, new modules were suggested. Our review identified 142 MSM studies with data from sSA, including 34 studies requiring module updates, one study contesting current content, and 107 studies reinforcing existing module content. ART adherence and community engagement were identified as new modules. Recent MSM studies conducted in sSA provided new knowledge, contested existing information, and identified new areas of MSM service needs currently unaddressed in the online training.
Scientific Publications
Cleavage independent HIV 1 Env trimers engineered as soluble native spike mimetics for vaccine design
Sharma SK, de Val N, Bale S, Guenaga J, Tran K, Feng Y, Dubrovskaya V, Ward AB, Wyatt RT
Cleavage-independent HIV-1 Env trimers engineered as soluble native spike mimetics for vaccine design. Cell Rep 2015;11(4):539-50 doi: 10.1016/j.celrep.2015.03.047
Abstract
Viral glycoproteins mediate entry by pH-activated or receptor-engaged activation and exist in metastable pre-fusogenic states that may be stabilized by directed rational design. As recently reported, the conformationally fixed HIV-1 envelope glycoprotein (Env) trimers in the pre-fusion state (SOSIP) display molecular homogeneity and structural integrity at relatively high levels of resolution. However, the SOSIPs necessitate full Env precursor cleavage, which requires endogenous furin overexpression. Here, we developed an alternative strategy using flexible peptide covalent linkage of Env subdomains to produce soluble, homogeneous, and cleavage-independent Env mimics, called native flexibly linked (NFL) trimers, as vaccine candidates. This simplified design avoids the need for furin co-expression and, in one case, antibody affinity purification to accelerate trimer scale-up for preclinical and clinical applications. We have successfully translated the NFL design to multiple HIV-1 subtypes, establishing the potential to become a general method of producing native-like, well-ordered Env trimers for HIV-1 or other viruses.
Scientific Publications
Knowledge of HIV serodiscordance transmission and prevention among couples in Durban South Africa
Kilembe W, Wall KM, Mokgoro M, Mwaanga A, Dissen E, Kamusoko M, Phiri H, Sakulanda J, Davitte J, Reddy T, Brockman M, Ndung'u T, Allen S
Knowledge of HIV serodiscordance, transmission, and prevention among couples in Durban, South Africa. PLoS ONE 2015;10(4):e0124548 doi: 10.1371/journal.pone.0124548
Abstract
Couples' voluntary HIV counseling and testing (CVCT) significantly decreases HIV transmission within couples, the largest risk group in sub-Saharan Africa, but it is not currently offered in most HIV testing facilities. To roll out such an intervention, understanding locale-specific knowledge barriers is critical. In this study, we measured knowledge of HIV serodiscordance, transmission, and prevention before and after receipt of CVCT services in Durban.
Scientific Publications
Immunogenetic influences on acquisition of HIV 1 infection consensus findings from two African cohorts point to an enhancer element in IL19 1q32 2
Li X, Zhang K, Pajewski NM, Brill I, Prentice HA, Shrestha S, Kilembe W, Karita E, Allen S, Hunter E, Kaslow RA, Tang J
Immunogenetic influences on acquisition of HIV-1 infection: consensus findings from two African cohorts point to an enhancer element in IL19 (1q32.2). Genes Immun. ;16(3):213-20 doi: 10.1038/gene.2014.84
doi: 10.1038/gene.2014.84
Abstract
Numerous reports have suggested that immunogenetic factors may influence human immunodeficiency virus (HIV)-1 acquisition, yet replicated findings that translate between study cohorts remain elusive. Our work aimed to test several hypotheses about genetic variants within the IL10-IL24 gene cluster that encodes interleukin (IL)-10, IL-19, IL-20 and IL-24. In aggregated data from 515 Rwandans and 762 Zambians with up to 12 years of follow-up, 190 single-nucleotide polymorphisms passed quality control procedures. When HIV-1-exposed seronegative subjects (n=486) were compared with newly seroconverted individuals (n=313) and seroprevalent subjects (n=478) who were already infected at enrollment, rs12407485 (G>A) in IL19 showed a robust association signal in adjusted logistic regression models (odds ratio=0.64, P=1.7 × 10(-4) and q=0.033). Sensitivity analyses demonstrated that (i) results from both cohorts and subgroups within each cohort were highly consistent; (ii) verification of HIV-1 infection status after enrollment was critical; and (iii) supporting evidence was readily obtained from Cox proportional hazards models. Data from public databases indicate that rs12407485 is part of an enhancer element for three transcription factors. Overall, these findings suggest that molecular features at the IL19 locus may modestly alter the establishment of HIV-1 infection.
Scientific Publications
Geographic and temporal trends in the molecular epidemiology and genetic mechanisms of transmitted HIV 1 drug resistance an individual patient and sequence level meta analysis
Rhee SY, Blanco JL, Jordan MR, Taylor J, Lemey P, Varghese V, Hamers RL, Bertagnolio S, Rinke de Wit TF, Aghokeng AF, Albert J, Avi R, Avila-Rios S, Bessong PO, Brooks JI, Boucher CA, Brumme ZL, Busch MP, Bussmann H, Chaix ML, Chin BS, D'Aquin TT, De Gascun CF, Derache A, Descamps D, Deshpande AK, Djoko CF, Eshleman SH, Fleury H, Frange P, Fujisaki S, Harrigan PR, Hattori J, Holguin A, Hunt GM, Ichimura H, Kaleebu P, Katzenstein D, Kiertiburanakul S, Kim JH, Kim SS, Li Y, Lutsar I, Morris L, Ndembi N, Ng KP, Paranjape RS, Peeters M, Poljak M, Price MA, Ragonnet-Cronin ML, Reyes-Terán G, Rolland M, Sirivichayakul S, Smith DM, Soares MA, Soriano VV, Ssemwanga D, Stanojevic M, Stefani MA, Sugiura W, Sungkanuparph S, Tanuri A, Tee KK, Truong HM, van de Vijver DA, Vidal N, Yang C, Yang R, Yebra G, Ioannidis JP, Vandamme AM, Shafer RW
Geographic and temporal trends in the molecular epidemiology and genetic mechanisms of transmitted HIV-1 drug resistance: an individual-patient- and sequence-level meta-analysis. PLoS Med. 2015;12(4):e1001810 doi: 10.1371/journal.pmed.1001810
Abstract
Regional and subtype-specific mutational patterns of HIV-1 transmitted drug resistance (TDR) are essential for informing first-line antiretroviral (ARV) therapy guidelines and designing diagnostic assays for use in regions where standard genotypic resistance testing is not affordable. We sought to understand the molecular epidemiology of TDR and to identify the HIV-1 drug-resistance mutations responsible for TDR in different regions and virus subtypes.
Scientific Publications
Crystal structure of the HIV neutralizing antibody 2G12 in complex with a bacterial oligosaccharide analog of mammalian oligomannose
Stanfield RL, De Castro C, Marzaioli AM, Wilson IA, Pantophlet R
Crystal structure of the HIV neutralizing antibody 2G12 in complex with a bacterial oligosaccharide analog of mammalian oligomannose. Glycobiology 2015;25(4):412-9 doi: 10.1093/glycob/cwu123
Abstract
Human immunodeficiency virus-1 (HIV-1) is a major public health threat that continues to infect millions of people worldwide each year. A prophylactic vaccine remains the most cost-effective way of globally reducing and eliminating the spread of the virus. The HIV envelope spike, which is the target of many vaccine design efforts, is densely mantled with carbohydrate and several potent broadly neutralizing antibodies to HIV-1 recognize carbohydrate on the envelope spike as a major part of their epitope. However, immunizing with recombinant forms of the envelope glycoprotein does not typically elicit anti-carbohydrate antibodies. Thus, studies of alternative antigens that may serve as a starting point for carbohydrate-based immunogens are of interest. Here, we present the crystal structure of one such anti-carbohydrate HIV neutralizing antibody (2G12) in complex with the carbohydrate backbone of the lipooligosaccharide from Rhizobium radiobacter strain Rv3, which exhibits a chemical structure that naturally mimics the core high-mannose carbohydrate epitope of 2G12 on HIV-1 gp120. The structure described here provides molecular evidence of the structural homology between the Rv3 oligosaccharide and highly abundant carbohydrates on the surface of HIV-1 and raises the potential for the design of novel glycoconjugates that may find utility in efforts to develop immunogens for eliciting carbohydrate-specific neutralizing antibodies to HIV.
Scientific Publications
An efficiently cleaved HIV 1 clade C Env selectively binds to neutralizing antibodies
Boliar S, Das S, Bansal M, Shukla BN, Patil S, Shrivastava T, Samal S, Goswami S, King CR, Bhattacharya J, Chakrabarti BK
An efficiently cleaved HIV-1 clade C Env selectively binds to neutralizing antibodies. PLoS ONE 2015;10(3):e0122443 doi: 10.1371/journal.pone.0122443
Abstract
An ideal HIV-1 Env immunogen is expected to mimic the native trimeric conformation for inducing broadly neutralizing antibody responses. The native conformation is dependent on efficient cleavage of HIV-1 Env. The clade B isolate, JRFL Env is efficiently cleaved when expressed on the cell surface. Here, for the first time, we report the identification of a native clade C Env, 4-2.J41 that is naturally and efficiently cleaved on the cell surface as confirmed by its biochemical and antigenic characteristics. In addition to binding to several conformation-dependent neutralizing antibodies, 4-2.J41 Env binds efficiently to the cleavage-dependent antibody PGT151; thus validating its native cleaved conformation. In contrast, 4-2.J41 Env occludes non-neutralizing epitopes. The cytoplasmic-tail of 4-2.J41 Env plays an important role in maintaining its conformation. Furthermore, codon optimization of 4-2.J41 Env sequence significantly increases its expression while retaining its native conformation. Since clade C of HIV-1 is the prevalent subtype, identification and characterization of this efficiently cleaved Env would provide a platform for rational immunogen design.