Africa-specific human genetic variation near CHD1L associates with HIV-1 load.

HIV-1 remains a global health crisis1, highlighting the need to identify new targets for therapies. Here, given the disproportionate HIV-1 burden and marked human genome diversity in Africa2, we assessed the genetic determinants of control of set-point viral load in 3,879 people of African ancestries living with HIV-1 participating in the international collaboration for the genomics of HIV3. We identify a previously undescribed association signal on chromosome 1 where the peak variant associates with an approximately 0.3 log10-transformed copies per ml lower set-point viral load per minor allele copy and is specific to populations of African descent. The top associated variant is intergenic and lies between a long intergenic non-coding RNA (LINC00624) and the coding gene CHD1L, which encodes a helicase that is involved in DNA repair4. Infection assays in iPS cell-derived macrophages and other immortalized cell lines showed increased HIV-1 replication in CHD1L-knockdown and CHD1L-knockout cells. We provide evidence from population genetic studies that Africa-specific genetic variation near CHD1L associates with HIV replication in vivo. Although experimental studies suggest that CHD1L is able to limit HIV infection in some cell types in vitro, further investigation is required to understand the mechanisms underlying our observations, including any potential indirect effects of CHD1L on HIV spread in vivo that our cell-based assays cannot recapitulate.

Rapid and Focused Maturation of a VRC01-Class HIV Broadly Neutralizing Antibody Lineage Involves Both Binding and Accommodation of the N276-Glycan.

The VH1-2 restricted VRC01-class of antibodies targeting the HIV envelope CD4 binding site are a major focus of HIV vaccine strategies. However, a detailed analysis of VRC01-class antibody development has been limited by the rare nature of these responses during natural infection and the lack of longitudinal sampling of such responses. To inform vaccine strategies, we mapped the development of a VRC01-class antibody lineage (PCIN63) in the subtype C infected IAVI Protocol C neutralizer PC063. PCIN63 monoclonal antibodies had the hallmark VRC01-class features and demonstrated neutralization breadth similar to the prototype VRC01 antibody, but were 2- to 3-fold less mutated. Maturation occurred rapidly within ∼24 months of emergence of the lineage and somatic hypermutations accumulated at key contact residues. This longitudinal study of broadly neutralizing VRC01-class antibody lineage reveals early binding to the N276-glycan during affinity maturation, which may have implications for vaccine design.

High throughput analysis of B cell dynamics and neutralizing antibody development during immunization with a novel clade C HIV-1 envelope.

A protective HIV-1 vaccine has been hampered by a limited understanding of how B cells acquire neutralizing activity. Our previous vaccines expressing two different HIV-1 envelopes elicited robust antigen specific serum IgG titers in 20 rhesus macaques; yet serum from only two animals neutralized the autologous virus. Here, we used high throughput immunoglobulin receptor and single cell RNA sequencing to characterize the overall expansion, recall, and maturation of antigen specific B cells longitudinally over 90 weeks. Diversification and expansion of many B cell clonotypes occurred broadly in the absence of serum neutralization. However, in one animal that developed neutralization, two neutralizing B cell clonotypes arose from the same immunoglobulin germline and were tracked longitudinally. Early antibody variants with high identity to germline neutralized the autologous virus while later variants acquired somatic hypermutation and increased neutralization potency. The early engagement of precursors capable of neutralization with little to no SHM followed by prolonged affinity maturation allowed the two neutralizing lineages to successfully persist despite many other antigen specific B cells. The findings provide new insight into B cells responding to HIV-1 envelope during heterologous prime and boost immunization in rhesus macaques and the development of selected autologous neutralizing antibody lineages.

Early Antibody Lineage Diversification and Independent Limb Maturation Lead to Broad HIV-1 Neutralization Targeting the Env High-Mannose Patch.

The high-mannose patch on HIV Env is a preferred target for broadly neutralizing antibodies (bnAbs), but to date, no vaccination regimen has elicited bnAbs against this region. Here, we present the development of a bnAb lineage targeting the high-mannose patch in an HIV-1 subtype-C-infected donor from sub-Saharan Africa. The Abs first acquired autologous neutralization, then gradually matured to achieve breadth. One Ab neutralized >47% of HIV-1 strains with only ∼11% somatic hypermutation and no insertions or deletions. By sequencing autologous env, we determined key residues that triggered the lineage and participated in Ab-Env coevolution. Next-generation sequencing of the Ab repertoire showed an early expansive diversification of the lineage followed by independent maturation of individual limbs, several of them developing notable breadth and potency. Overall, the findings are encouraging from a vaccine standpoint and suggest immunization strategies mimicking the evolution of the entire high-mannose patch and promoting maturation of multiple diverse Ab pathways.

A neutralizing antibody target in early HIV-1 infection was recapitulated in rhesus macaques immunized with the transmitted/founder envelope sequence.

Transmitted/founder (T/F) HIV-1 envelope proteins (Envs) from infected individuals that developed neutralization breadth are likely to possess inherent features desirable for vaccine immunogen design. To explore this premise, we conducted an immunization study in rhesus macaques (RM) using T/F Env sequences from two human subjects, one of whom developed potent and broad neutralizing antibodies (Z1800M) while the other developed little to no neutralizing antibody responses (R66M) during HIV-1 infection. Using a DNA/MVA/protein immunization protocol, 10 RM were immunized with each T/F Env. Within each T/F Env group, the protein boosts were administered as either monomeric gp120 or stabilized trimeric gp140 protein. All vaccination regimens elicited high titers of antigen-specific IgG, and two animals that received monomeric Z1800M Env gp120 developed autologous neutralizing activity. Using early Env escape variants isolated from subject Z1800M as guides, the serum neutralizing activity of the two immunized RM was found to be dependent on the gp120 V5 region. Interestingly, the exact same residues of V5 were also targeted by a neutralizing monoclonal antibody (nmAb) isolated from the subject Z1800M early in infection. Glycan profiling and computational modeling of the Z1800M Env gp120 immunogen provided further evidence that the V5 loop is exposed in this T/F Env and was a dominant feature that drove neutralizing antibody targeting during infection and immunization. An expanded B cell clonotype was isolated from one of the neutralization-positive RM and nmAbs corresponding to this group demonstrated V5-dependent neutralization similar to both the RM serum and the human Z1800M nmAb. The results demonstrate that neutralizing antibody responses elicited by the Z1800M T/F Env in RM converged with those in the HIV-1 infected human subject, illustrating the potential of using immunogens based on this or other T/F Envs with well-defined immunogenicity as a starting point to drive breadth.

Use of "Strengthening Our Vows" Video Intervention to Encourage Negotiated Explicit Sexual Agreements in Zambian Heterosexual HIV Seroconcordant-Negative Couples.

Negotiating sexual agreements in combination with couples' voluntary HIV counseling and testing (CVCT) may help further reduce HIV transmission in Zambian concordant HIV-negative couples (CNC). Though CVCT has been shown to reduce HIV transmission in CNC by 47%, approximately half of residual infections occur in this group. We developed a "Strengthening Our Vows" video session to foster communication and negotiation of explicit sexual agreements to reduce concurrent sexual exposures and prevent HIV transmission to the spouse due to unprotected, extramarital sex. CNC were recruited through CVCT services at five clinics in Lusaka and Ndola in 2016. Enrolled CNC attending the facilitated group video sessions were encouraged to discuss sexual agreements at home and return 1-2 weeks later for follow-up assessment. One-fourth of the 580 CNC returning reported a history of extramarital partners and/or a sexually transmitted infection (STI) prior to enrollment. More than 95% reported a friendly, supportive 15-60 min negotiation culminating in an agreement to remain monogamous or disclose sexual contacts and use condoms together until a repeat HIV test 30 days after an outside sexual exposure. Two-thirds of participants identified at least one threat to adherence of their agreements including alcohol use, financial pressures, travel, discord in the home, and post-partum or menstrual abstinence. CNC negotiated explicit sexual agreements to avoid exposure to HIV through concurrent partnerships and protect the spouse in the event of an outside sexual contact. Open communication was a consistent theme to facilitate mutual protective efforts. Long-term follow-up of HIV/STI incidence is ongoing to assess the impact of these agreements.Trial registration This sub-study is part of a trial retrospectively registered on ClinicalTrials.gov (Identifier: NCT02744586) on April 20, 2016.

HIV-1 variants are archived throughout infection and persist in the reservoir.

The HIV-1 reservoir consists of latently infected cells that persist despite antiretroviral therapy (ART). Elucidating the proviral genetic composition of the reservoir, particularly in the context of pre-therapy viral diversity, is therefore important to understanding reservoir formation and the persistence of latently infected cells. Here we investigate reservoir proviral variants from 13 Zambian acutely-infected individuals with additional pre-therapy sampling for a unique comparison to the ART-naïve quasispecies. We identified complete transmitted/founder (TF) viruses from seroconversion plasma samples, and additionally amplified and sequenced HIV-1 from plasma obtained one year post-infection and just prior to ART initiation. While the majority of proviral variants in the reservoir were most closely related to viral variants from the latest pre-therapy time point, we also identified reservoir proviral variants dating to or near the time of infection, and to intermediate time points between infection and treatment initiation. Reservoir proviral variants differing by five or fewer nucleotide changes from the TF virus persisted during treatment in five individuals, including proviral variants that exactly matched the TF in two individuals, one of whom had remained ART-naïve for more than six years. Proviral variants during treatment were significantly less divergent from the TF virus than plasma variants present at the last ART-naïve time point. These findings indicate that reservoir proviral variants are archived throughout infection, recapitulating much of the viral diversity that arises throughout untreated HIV-1 infection, and strategies to target and reduce the reservoir must therefore permit for the clearance of proviruses encompassing this extensive diversity.

Evolution of Condom Use Among a 5-Year Cohort of Female Sex Workers in Zambia.

Observing sexual behaviour change over time could help develop behavioural HIV prevention interventions for female sex workers in Zambia, where these interventions are lacking. We investigated the evolution of consistent condom use among female sex workers and their clients and steady partners. Participants were recruited into an HIV incidence cohort from 2012 to 2017. At each visit, women received HIV counselling and testing, screening for sexually transmitted infections (STIs) and free condoms. Our outcome was reported consistent (100%) condom use in the previous month with steady partners, repeat clients, and non-repeat clients. Consistent condom use at baseline was highest with non-repeat clients (36%) followed by repeat clients (27%) and steady partners (17%). Consistent condom use between baseline and Month 42 increased by 35% with steady partners, 39% with repeat clients and 41% with non-repeat clients. Access to condoms, HIV/STI counselling and testing promoted positive sexual behaviour change.

A Stronger Innate Immune Response During Hyperacute Human Immunodeficiency Virus Type 1 (HIV-1) Infection Is Associated With Acute Retroviral Syndrome.

BACKGROUND: Acute retroviral syndrome (ARS) is associated with human immunodeficiency virus type 1 (HIV-1) subtype and disease progression, but the underlying immunopathological pathways are poorly understood. We aimed to elucidate associations between innate immune responses during hyperacute HIV-1 infection (hAHI) and ARS. METHODS: Plasma samples obtained from volunteers (≥18.0 years) before and during hAHI, defined as HIV-1 antibody negative and RNA or p24 antigen positive, from Kenya, Rwanda, Uganda, Zambia, and Sweden were analyzed. Forty soluble innate immune markers were measured using multiplexed assays. Immune responses were differentiated into volunteers with stronger and comparatively weaker responses using principal component analysis. Presence or absence of ARS was defined based on 11 symptoms using latent class analysis. Logistic regression was used to determine associations between immune responses and ARS. RESULTS: Of 55 volunteers, 31 (56%) had ARS. Volunteers with stronger immune responses (n = 36 [65%]) had increased odds of ARS which was independent of HIV-1 subtype, age, and risk group (adjusted odds ratio, 7.1 [95% confidence interval {CI}: 1.7-28.8], P = .003). Interferon gamma-induced protein (IP)-10 was 14-fold higher during hAHI, elevated in 7 of the 11 symptoms and independently associated with ARS. IP-10 threshold >466.0 pg/mL differentiated stronger immune responses with a sensitivity of 84.2% (95% CI: 60.4-96.6) and specificity of 100.0% (95% CI]: 90.3-100.0). CONCLUSIONS: A stronger innate immune response during hAHI was associated with ARS. Plasma IP-10 may be a candidate biomarker of stronger innate immunity. Our findings provide further insights on innate immune responses in regulating ARS and may inform the design of vaccine candidates harnessing innate immunity.

Elevated levels of inflammatory plasma biomarkers are associated with risk of HIV infection.

BACKGROUND: To determine if individuals, from HIV-1 serodiscordant couple cohorts from Rwanda and Zambia, who become HIV-positive have a distinct inflammatory biomarker profile compared to individuals who remain HIV-negative, we compared levels of biomarkers in plasma of HIV-negative individuals who either seroconverted (pre-infection) and became HIV-positive or remained HIV-negative (uninfected). RESULTS: We observed that individuals in the combined cohort, as well as those in the individual country cohorts, who later became HIV-1 infected had significantly higher baseline levels of multiple inflammatory cytokines/chemokines compared to individuals who remained HIV-negative. Genital inflammation/ulceration or schistosome infections were not associated with this elevated profile. Defined levels of ITAC and IL-7 were significant predictors of later HIV acquisition in ROC predictive analyses, whereas the classical Th1 and Th2 inflammatory cytokines such as IL-12 and interferon-γ or IL-4, IL-5 and Il-13 were not. CONCLUSIONS: Overall, the data show a significant association between increased plasma biomarkers linked to inflammation and immune activation and HIV acquisition and suggests that pre-existing conditions that increase systemic biomarkers represent a factor for increased risk of HIV infection.

Better Viral Control despite Higher CD4+ T Cell Activation during Acute HIV-1 Infection in Zambian Women Is Linked to the Sex Hormone Estradiol.

The influence of biological sex on disease progression in HIV-1-infected individuals has been focused on the chronic stage of infection, but little is known about how sex differences influence acute HIV-1 infection. We observed profound differences in viral load and CD4+ T cell activation from the earliest time points in men and women in a Zambian heterosexual acute infection cohort. Women exhibited a >2-fold higher rate of CD4+ T cell loss despite significantly lower viral loads (VL) than men. The importance of studying acute infection was highlighted by the observation that very early in infection, women exhibited significantly higher levels of CD4+ T cell activation, a difference that was lost over the first 3 years of infection as activation in men increased. In women, activation of CD4+ T cells in the acute phase was significantly correlated with plasma levels of 17ß-estradiol (E2). However, unlike in men, higher CD4+ T cell activation in women was not associated with higher VL. In contrast, a higher E2 level in early infection was associated with lower early and set-point VL in women. We attribute this to an inhibitory effect of estradiol on virus replication, which we were able to observe with relevant transmitted/founder viruses in vitro Thus, estradiol plays a key role in defining major differences between men and women during early HIV-1 infection by contributing to both viral control and CD4+ T cell loss, an effect that extends into the chronic phase of the disease.IMPORTANCE Previous studies have identified sex-specific differences during chronic HIV-1 infection, but little is known about sex differences in the acute phase, or how disparities in the initial response to the virus may affect disease. We demonstrate that restriction of viral load in women begins during acute infection and is maintained into chronic infection. Despite this, women exhibit more rapid CD4+ T cell loss than men. These profound differences are influenced by 17ß-estradiol, which contributes both to T cell activation and to reduced viral replication. Thus, we conclude that estradiol plays a key role in shaping responses to early HIV-1 infection that influence the chronic phase of disease.

Protective HLA alleles are associated with reduced LPS levels in acute HIV infection with implications for immune activation and pathogenesis.

Despite extensive research on the mechanisms of HLA-mediated immune control of HIV-1 pathogenesis, it is clear that much remains to be discovered, as exemplified by protective HLA alleles like HLA-B*81 which are associated with profound protection from CD4+ T cell decline without robust control of early plasma viremia. Here, we report on additional HLA class I (B*1401, B*57, B*5801, as well as B*81), and HLA class II (DQB1*02 and DRB1*15) alleles that display discordant virological and immunological phenotypes in a Zambian early infection cohort. HLA class I alleles of this nature were also associated with enhanced immune responses to conserved epitopes in Gag. Furthermore, these HLA class I alleles were associated with reduced levels of lipopolysaccharide (LPS) in the plasma during acute infection. Elevated LPS levels measured early in infection predicted accelerated CD4+ T cell decline, as well as immune activation and exhaustion. Taken together, these data suggest novel mechanisms for HLA-mediated immune control of HIV-1 pathogenesis that do not necessarily involve significant control of early viremia and point to microbial translocation as a direct driver of HIV-1 pathogenesis rather than simply a consequence.

A Population-Specific Optimized GeneXpert Pooling Algorithm for Chlamydia trachomatis and Neisseria gonorrhoeae To Reduce Cost of Molecular Sexually Transmitted Infection Screening in Resource-Limited Settings.

The sexually transmitted infections (STIs) chlamydia (CT) and gonorrhea (NG) are often asymptomatic in women and undetected by syndromic management, leading to complications such as pelvic inflammatory disease, infertility, and ectopic pregnancy. Molecular testing, such as the GeneXpert CT/NG assay, is highly sensitive, but cost restraints preclude implementation of these technologies in resource-limited settings. Pooled testing is one strategy to reduce the cost per sample, but the extent of savings depends on disease prevalence. The current study describes a pooling strategy based on identification of sociodemographic and laboratory factors associated with CT/NG prevalence in a high-risk cohort of Zambian female sex workers and single mothers conducted from 2016 to 2019. Factors associated with testing positive for CT/NG via logistic regression modeling included city, younger age, lower education, long-acting reversible contraception usage, Trichomonas vaginalis infection, bacterial vaginosis, and incident syphilis infection. Based on these factors, the study population was stratified into high-, intermediate-, and low-prevalence subgroups and tested accordingly-individually, pools of 3, or pools of 4, respectively. The cost per sample was reduced from $18 to as low as $9.43 in the low-prevalence subgroup. The checklist tool and pooling approach described can be used in a variety of treatment algorithms to lower the cost per sample and increase access to molecular STI screening. This is particularly valuable in resource-limited settings to detect and treat asymptomatic CT/NG infections missed by traditional syndromic management.

Fertility intentions and long-acting reversible contraceptive use among HIV-negative single mothers in Zambia.

BACKGROUND: Integrating family planning interventions with HIV studies in developing countries has been shown to prevent mother-to-child HIV transmission and simultaneously reduce HIV and unintended pregnancy in high-risk populations. As part of a prospective cohort study on HIV incidence and risk factors in Zambian women having unprotected sex, we also offered family planning counseling and immediate access to long-acting reversible contraceptives. Although long-acting reversible contraceptives are the most effective form of contraception, many Zambian women are limited to oral or injectable methods because of a lack of knowledge or method availability. This project offers to single mothers who are enrolled in a cohort study information about and access to long-acting reversible contraceptives at enrollment and at each follow-up visit. OBJECTIVE: This study evaluates how fertility intentions affect long-acting reversible contraceptive use in HIV-negative single mothers in Zambia. Our primary outcome was long-acting reversible contraceptive use throughout the study participation. We also estimated rates of long-acting reversible contraceptive uptake and discontinuation. We specifically studied single mothers because they are at high risk for unintended pregnancy, which can have significant negative ramifications on their financial, social, and psychologic circumstances. STUDY DESIGN: From 2012-2017, Zambia Emory HIV Research Project recruited 521 HIV-negative single mothers ages 18-45 years from government clinics in Lusaka and Ndola, Zambia's 2 largest cities. Participants were followed every 3 months for up to 5 years. At each visit, we discussed fertility goals and contraceptive options and offered a long-acting reversible method to any woman who was not pregnant or who already was using a long-acting reversible or permanent contraceptive method. Data were collected on demographic factors, sexual behavior, and reproductive history. Multivariable logistic regression was used to model baseline fertility intentions with long-acting reversible contraceptive use. RESULTS: We enrolled 518 women; 57 women did not return for any follow-up visits. There was a significant increase in long-acting reversible contraceptive use during the study. At baseline, 93 of 518 women (18%) were using a long-acting reversible method, and 151 of 461 women (33%) used a long-acting reversible method at the end of follow-up period (P<.0001). Four women chose an intrauterine device, and 91 women chose an implant for their first uptake event. After we adjusted the data for other confounders, we found that women in Ndola who did not desire any more children were more likely to use a long-acting reversible contraceptive (adjusted prevalence ratio, 2.02; 95% confidence interval, 1.88-3.42). During follow up, 37 of 183 long-acting reversible contraceptive users (20%) discontinued their method; women who desired future children at baseline were more likely to discontinue earlier (P=.016). CONCLUSION: This study demonstrates that integrated family planning services can increase long-acting reversible contraceptive use successfully among Zambian single mothers, who are a vulnerable population that disproportionately is affected by unintended pregnancy. A steady increase in use over time confirms the importance of repeated messaging about these unfamiliar methods. Thus, it is imperative that family planning interventions target single mothers in developing countries to promote effective contraceptive use.

A couple-focused, integrated unplanned pregnancy and HIV prevention program in urban and rural Zambia.

BACKGROUND: Zambia's total fertility rate (5 births per woman) and adult HIV prevalence (11.5%) are among the highest in the world, with heterosexual couples being the most affected group. Jointly counseling and testing couples for HIV has reduced up to 58% of new HIV infections in Zambian clinics. Married women using contraceptives in Zambia have a high (20%) unmet need for family planning and low (8.6%) uptake of cost-effective long-acting reversible contraceptives. We present an integrated counseling, testing, and family-planning program to prevent HIV and unplanned pregnancy in Zambia. OBJECTIVE: The objective of this study was to integrate effective HIV prevention and family-planning services for Zambian couples. STUDY DESIGN: A 3 year program (2013-2016) progressively integrated the promotion and provision of couples' voluntary HIV counseling and testing and long-acting reversible contraceptives. The program was based in 55 urban and 215 rural government clinics across 33 districts. In the first year, a couples' family-planning counseling training program was developed and combined with existing couples HIV counseling training materials. To avoid congestion during routine clinic hours, joint counseling services were initially provided on weekends, while nurses were trained in intrauterine device and hormonal implant insertion and removal during weekday family-planning services. Demand was created through mutual referral between weekend and weekday programs and by clinic staff, community health workers, and satisfied family-planning clients. When the bulk of integrated service training was completed, the program transitioned services to routine weekday clinic hours, ensuring access to same-day services. Performance indicators included number of staff trained, clients served, integrated service referrals, HIV infections averted, and unplanned pregnancies averted. RESULTS: A stepwise approach trained high-performing service providers to be trainers and used high-volume clinics for practicum training of the next generation. In total, 1201 (391 urban, 810 rural) counselors were trained and served 120,535 urban and 87,676 rural couples. In urban clinics, 236 nurses inserted 65,619 long-acting reversible contraceptives, while in rural clinics, 243 nurses inserted 35,703 implants and intrauterine devices. The program prevented an estimated 12,869 urban and 8279 rural adult HIV infections, and 98,626 unintended urban pregnancies. In the final year, the proportion of clients receiving joint counseling services on weekdays rose from 11% to 89%, with many referred from within clinics including HIV testing and treatment services (32%), outpatient department (31%), family planning (16%), and infant vaccination (15%). The largest group of clients requesting long-acting reversible contraceptives (45%) did so after joint fertility goal-based counseling, confirming the high impact of this couple-focused demand creation approach. Remaining family-planning clients responded to referrals from clinic nurses (34%), satisfied implant/intrauterine device users (13%), or community health workers (8%). CONCLUSION: Integrated HIV and unplanned pregnancy prevention can be implemented in low-resource public sector facilities. Combination services offered to couples mutually leverage HIV prevention and unplanned pregnancy prevention. The addition of long-acting reversible contraceptives is an important complement to the method mix available in government clinics. Demand creation in the clinic and in the community must be coordinated with a growing supply of well-trained providers.

African-led health research and capacity building- is it working?

BACKGROUND: Africa bears a disproportionately high burden of globally significant disease but has lagged in knowledge production to address its health challenges. In this contribution, we discuss the challenges and approaches to health research capacity strengthening in sub-Saharan Africa and propose that the recent shift to an African-led approach is the most optimal. METHODS AND FINDINGS: We introduce several capacity building approaches and recent achievements, explore why African-led research on the continent is a potentially paradigm-shifting and innovative approach, and discuss the advantages and challenges thereof. We reflect on the approaches used by the African Academy of Sciences (AAS)-funded Sub-Saharan African Network for TB/HIV Research Excellence (SANTHE) consortium as an example of an effective African-led science and capacity building programme. We recommend the following as crucial components of future efforts: 1. Directly empowering African-based researchers, 2. Offering quality training and career development opportunities to large numbers of junior African scientists and support staff, and 3. Effective information exchange and collaboration. Furthermore, we argue that long-term investment from international donors and increasing funding commitments from African governments and philanthropies will be needed to realise a critical mass of local capacity and to create and sustain world-class research hubs that will be conducive to address Africa's intractable health challenges. CONCLUSIONS: Our experiences so far suggest that African-led research has the potential to overcome the vicious cycle of brain-drain and may ultimately lead to improvement of health and science-led economic transformation of Africa into a prosperous continent.

Loss to follow-up among female sex workers in Zambia: findings from a five-year HIV-incidence cohort.

HIV-incidence studies are used to identify at-risk populations for HIV-prevention trials and interventions, but loss to follow-up (LTFU) can bias results if participants who remain differ from those who drop out. We investigated the incidence of and factors associated with LTFU among Zambian female sex workers (FSWs) in an HIV-incidence cohort from 2012 to 2017. Enrolled participants returned at month one, month three and quarterly thereafter. FSWs were considered LTFU if they missed six consecutive months, or if their last visit was six months before the study end date. Of 420 FSWs, 139 (33%) were LTFU at a rate of 15.7 per 100 person years. In multivariable analysis, LTFU was greater for FSWs who never used alcohol, began sex work above the age of consent, and had a lower volume of new clients. Our study appeared to retain FSWs in most need of HIV-prevention services offered at follow-up.

Control of the HIV-1 Load Varies by Viral Subtype in a Large Cohort of African Adults With Incident HIV-1 Infection.

Few human immunodeficiency virus (HIV)-infected persons can maintain low viral levels without therapeutic intervention. We evaluate predictors of spontaneous control of the viral load (hereafter, "viral control") in a prospective cohort of African adults shortly after HIV infection. Viral control was defined as ≥2 consecutively measured viral loads (VLs) of ≤10 000 copies/mL after the estimated date of infection, followed by at least 4 subsequent measurements for which the VL in at least 75% was ≤10 000 copies/mL in the absence of ART. Multivariable logistic regression characterized predictors of viral control. Of 590 eligible volunteers, 107 (18.1%) experienced viral control, of whom 25 (4.2%) maintained a VL of 51-2000 copies/mL, and 5 (0.8%) sustained a VL of ≤50 copies/mL. The median ART-free follow-up time was 3.3 years (range, 0.3-9.7 years). Factors independently associated with control were HIV-1 subtype A (reference, subtype C; adjusted odds ratio [aOR], 2.1 [95% confidence interval {CI}, 1.3-3.5]), female sex (reference, male sex; aOR, 1.8 [95% CI, 1.1-2.8]), and having HLA class I variant allele B*57 (reference, not having this allele; aOR, 1.9 [95% CI, 1.0-3.6]) in a multivariable model that also controlled for age at the time of infection and baseline CD4+ T-cell count. We observed strong associations between infecting HIV-1 subtype, HLA type, and sex on viral control in this cohort. HIV-1 subtype is important to consider when testing and designing new therapeutic and prevention technologies, including vaccines.

HLA Class I Downregulation by HIV-1 Variants from Subtype C Transmission Pairs.

HIV-1 downregulates human leukocyte antigen A (HLA-A) and HLA-B from the surface of infected cells primarily to evade CD8 T cell recognition. HLA-C was thought to remain on the cell surface and bind inhibitory killer immunoglobulin-like receptors, preventing natural killer (NK) cell-mediated suppression. However, a recent study found HIV-1 primary viruses have the capacity to downregulate HLA-C. The goal of this study was to assess the heterogeneity of HLA-A, HLA-B, and HLA-C downregulation among full-length primary viruses from six chronically infected and six newly infected individuals from transmission pairs and to determine whether transmitted/founder variants exhibit common HLA class I downregulation characteristics. We measured HLA-A, HLA-B, HLA-C, and total HLA class I downregulation by flow cytometry of primary CD4 T cells infected with 40 infectious molecular clones. Primary viruses mediated a range of HLA class I downregulation capacities (1.3- to 6.1-fold) which could differ significantly between transmission pairs. Downregulation of HLA-C surface expression on infected cells correlated with susceptibility to in vitro NK cell suppression of virus release. Despite this, transmitted/founder variants did not share a downregulation signature and instead were more similar to the quasispecies of matched donor partners. These data indicate that a range of viral abilities to downregulate HLA-A, HLA-B, and HLA-C exist within and between individuals that can have functional consequences on immune recognition.IMPORTANCE Subtype C HIV-1 is the predominant subtype involved in heterosexual transmission in sub-Saharan Africa. Authentic subtype C viruses that contain natural sequence variations throughout the genome often are not used in experimental systems due to technical constraints and sample availability. In this study, authentic full-length subtype C viruses, including transmitted/founder viruses, were examined for the ability to disrupt surface expression of HLA class I molecules, which are central to both adaptive and innate immune responses to viral infections. We found that the HLA class I downregulation capacity of primary viruses varied, and HLA-C downregulation capacity impacted viral suppression by natural killer cells. Transmitted viruses were not distinct in the capacity for HLA class I downregulation or natural killer cell evasion. These results enrich our understanding of the phenotypic variation existing among natural HIV-1 viruses and how that might impact the ability of the immune system to recognize infected cells in acute and chronic infection.