HLA-A*23 Is Associated With Lower Odds of Acute Retroviral Syndrome in Human Immunodeficiency Virus Type 1 Infection: A Multicenter Sub-Saharan African Study.

The role of human leukocyte antigen (HLA) class I and killer immunoglobulin-like receptor molecules in mediating acute retroviral syndrome (ARS) during human immunodeficiency virus type 1 (HIV-1) infection is unclear. Among 72 sub-Saharan African adults, HLA-A*23 was associated with lower odds of ARS (adjusted odds ratio, 0.10 [95% confidence interval, .01-.48]; P = .009), which warrants further studies to explore its role on HIV-1-specific immunopathogenesis.

HIV-2 mediated effects on target and bystander cells induce plasma proteome remodeling.

Despite low or undetectable plasma viral load, people living with HIV-2 (PLWH2) typically progress toward AIDS. The driving forces behind HIV-2 disease progression and the role of viremia are still not known, but low-level replication in tissues is believed to play a role. To investigate the impact of viremic and aviremic HIV-2 infection on target and bystander cell pathology, we used data-independent acquisition mass spectrometry to determine plasma signatures of tissue and cell type engagement. Proteins derived from target and bystander cells in multiple tissues, such as the gastrointestinal tract and brain, were detected at elevated levels in plasma of PLWH2, compared with HIV negative controls. Moreover, viremic HIV-2 infection appeared to induce enhanced release of proteins from a broader range of tissues compared to aviremic HIV-2 infection. This study expands the knowledge on the link between plasma proteome remodeling and the pathological cell engagement in tissues during HIV-2 infection.

Temporal trends and transmission dynamics of pre-treatment HIV-1 drug resistance within and between risk groups in Kenya, 1986-2020.

BACKGROUND: Evidence on the distribution of pre-treatment HIV-1 drug resistance (HIVDR) among risk groups is limited in Africa. We assessed the prevalence, trends and transmission dynamics of pre-treatment HIVDR within and between MSM, people who inject drugs (PWID), female sex workers (FSWs), heterosexuals (HETs) and perinatally infected children in Kenya. METHODS: HIV-1 partial pol sequences from antiretroviral-naive individuals collected from multiple sources between 1986 and 2020 were used. Pre-treatment reverse transcriptase inhibitor (RTI), PI and integrase inhibitor (INSTI) mutations were assessed using the Stanford HIVDR database. Phylogenetic methods were used to determine and date transmission clusters. RESULTS: Of 3567 sequences analysed, 550 (15.4%, 95% CI: 14.2-16.6) had at least one pre-treatment HIVDR mutation, which was most prevalent amongst children (41.3%), followed by PWID (31.0%), MSM (19.9%), FSWs (15.1%) and HETs (13.9%). Overall, pre-treatment HIVDR increased consistently, from 6.9% (before 2005) to 24.2% (2016-20). Among HETs, pre-treatment HIVDR increased from 6.6% (before 2005) to 20.2% (2011-15), but dropped to 6.5% (2016-20). Additionally, 32 clusters with shared pre-treatment HIVDR mutations were identified. The majority of clusters had R0 ≥ 1.0, indicating ongoing transmissions. The largest was a K103N cluster involving 16 MSM sequences sampled between 2010 and 2017, with an estimated time to the most recent common ancestor (tMRCA) of 2005 [95% higher posterior density (HPD), 2000-08], indicating propagation over 12 years. CONCLUSIONS: Compared to HETs, children and key populations had higher levels of pre-treatment HIVDR. Introduction of INSTIs after 2017 may have abrogated the increase in pre-treatment RTI mutations, albeit in the HET population only. Taken together, our findings underscore the need for targeted efforts towards equitable access to ART for children and key populations in Kenya.

Exposure to common infections may shape basal immunity and potentially HIV-1 acquisition amongst a high-risk population in Coastal Kenya.

Introduction: The impact of exposure to endemic infections on basal immunity and susceptibility to HIV-1 acquisition remains uncertain. We hypothesized that exposure to infections such as cytomegalovirus (CMV), malaria and sexually transmitted infections (STIs) in high-risk individuals may modulate immunity and subsequently increase susceptibility to HIV-1 acquisition. Methods: A case-control study nested in an HIV-1 negative high-risk cohort from Coastal Kenya was used. Cases were defined as volunteers who tested HIV-1 positive during follow-up and had a plasma sample collected 3 ± 2 months prior to the estimated date of HIV-1 infection. Controls were individuals who remained HIV-1 negative during the follow-up and were matched 2:1 to cases by sex, age, risk group and follow-up time. STI screening was performed using microscopic and serologic tests. HIV-1 pre-infection plasma samples were used to determined exposure to CMV and malaria using enzyme-linked immunosorbent assays and to quantify forty-one cytokines and soluble factors using multiplexing assays. Multiplexing data were analyzed using principal component analysis. Associations between cytokines and soluble factors with subsequent HIV-1 acquisition were determined using conditional logistic regression models. Results and discussion: Overall, samples from 47 cases and 94 controls were analyzed. While exposure to malaria (p=0.675) and CMV (p=0.470) were not associated with HIV-1 acquisition, exposure to STIs was (48% [95% CI, 33.3 - 63] vs. 26% [95% CI, 17.3 - 35.9]. Ten analytes were significantly altered in cases compared to controls and were clustered into four principal components: PC1 (VEGF, MIP-1ß, VEGF-C and IL-4), PC2 (MCP-1, IL-2 and IL-12p70), PC3 (VEGF-D) and PC4 (Eotaxin-3). PC1, which is suggestive of a Th2-modulatory pathway, was significantly associated with HIV-1 acquisition after controlling for STIs (adjusted odds ratio, (95% CI), p-value: 1.51 [1.14 - 2.00], p=0.004). Elevation of Th2-associated pathways may dampen responses involved in viral immunity, leading to enhanced susceptibility to HIV-1 acquisition. Immunomodulatory interventions aimed at inhibiting activation of Th2-associated pathways may be an additional strategy to STI control for HIV-1 prevention and may reduce dampening of immune responses to vaccination.

Intra-Patient Evolution of HIV-2 Molecular Properties.

Limited data are available on the pathogenesis of HIV-2, and the evolution of Env molecular properties during disease progression is not fully elucidated. We investigated the intra-patient evolution of molecular properties of HIV-2 Env regions (V1-C3) during the asymptomatic, treatment-naïve phase of the infection in 16 study participants, stratified into faster or slower progressors. Most notably, the rate of change in the number of potential N-linked glycosylation sites (PNGS) within the Env (V1-C3) regions differed between progressor groups. With declining CD4+ T-cell levels, slower progressors showed, on average, a decrease in the number of PNGSs, while faster progressors showed no significant change. Furthermore, diversity increased significantly with time in faster progressors, whereas no such change was observed in slower progressors. No differences were identified between the progressor groups in the evolution of length or charge of the analyzed Env regions. Predicted virus CXCR4 use was rare and did not emerge as a dominating viral population during the studied disease course (median 7.9 years, interquartile range [IQR]: 5.2-14.0) in either progressor groups. Further work building on our observations may explain molecular hallmarks of HIV-2 disease progression and differences in pathogenesis between HIV-1 and HIV-2.

Hierarchical Clustering and Trajectory Analyses Reveal Viremia-Independent B-Cell Perturbations in HIV-2 Infection.

Time to AIDS in HIV-2 infection is approximately twice as long compared to in HIV-1 infection. Despite reduced viremia, HIV-2-infected individuals display signs of chronic immune activation. In HIV-1-infected individuals, B-cell hyperactivation is driven by continuous antigen exposure. However, the contribution of viremia to B-cell perturbations in HIV-2-infected individuals remains largely unexplored. Here, we used polychromatic flow cytometry, consensus hierarchical clustering and pseudotime trajectory inference to characterize B-cells in HIV-1- or HIV-2-infected and in HIV seronegative individuals. We observed increased frequencies of clusters containing hyperactivated T-bethighCD95highCD27int and proliferating T-bet+CD95highCD27+CD71+ memory B-cells in viremic HIV-1 (p < 0.001 and p < 0.001, respectively), viremic HIV-2 (p < 0.001 and p = 0.014, respectively) and in treatment-naïve aviremic HIV-2 (p = 0.004 and p = 0.020, respectively)-infected individuals, compared to seronegative individuals. In contrast, these expansions were not observed in successfully treated HIV-1-infected individuals. Finally, pseudotime trajectory inference showed that T-bet-expressing hyperactivated and proliferating memory B-cell populations were located at the terminal end of two trajectories, in both HIV-1 and HIV-2 infections. As the treatment-naïve aviremic HIV-2-infected individuals, but not the successfully ART-treated HIV-1-infected individuals, showed B-cell perturbations, our data suggest that aviremic HIV-2-infected individuals would also benefit from antiretroviral treatment.

Phylogenetic Characterization of HIV-1 Sub-Subtype A1 in Karachi, Pakistan.

(1) Background: HIV-1 sub-subtype A1 is common in parts of Africa, Russia, former Soviet Union countries, and Eastern Europe. In Pakistan, sub-subtype A1 is the predominant HIV-1 subtype. Preliminary evidence suggests that distinct strains of HIV-1 sub-subtype A1 are circulating in Pakistan; however, an in-depth molecular phylogenetic characterization of HIV-1 sub-subtype A1 strains in Pakistan have not been presented. We performed a detailed characterization of the HIV-1 sub-subtype A1 epidemic in Pakistan using state-of-the-art molecular epidemiology and phylodynamics. (2) Methods: A total of 143 HIV-1 sub-subtype A1 gag sequences, including 61 sequences generated specifically for this study from PLHIVs part of our cohort, representing all sub-subtype A1 gag sequences from Pakistan, were analyzed. Maximum-likelihood phylogenetic cluster analysis was used to determine the relationship between Pakistani sub-subtype A1 strains and pandemic sub-subtype A1 strains. Furthermore, we used signature variation, charge distribution, selection pressures, and epitope prediction analyses to characterize variations unique to Pakistani HIV-1 strains and establish the association between signature variations and Gag epitope profile. (3) Results: The HIV-1 sub-subtype A1 sequences from Pakistan formed three main clusters: two that clustered with Kenyan sequences (7 and 10 sequences, respectively) and one that formed a Pakistan-specific cluster of 123 sequences that were much less related to other sub-subtype A1 sequences available in the database. The sequences in the Pakistan-specific cluster and the Kenyan reference strains exhibited several signature variations, especially at amino acid positions 312, 319, 331, 372, 373, 383, and 402. Structural protein modeling suggested that amino acid changes in these positions result in alterations of the Gag protein structure as well as in Gag-specific T-cell epitopes. (4) Conclusions: Our results suggest that the majority of the Pakistan HIV-1 sub-subtype A1 strains were unique to Pakistan and with a specific mutation pattern in Gag.

Phylogeographic Assessment Reveals Geographic Sources of HIV-1 Dissemination Among Men Who Have Sex With Men in Kenya.

HIV-1 transmission dynamics involving men who have sex with men (MSM) in Africa are not well understood. We investigated the rates of HIV-1 transmission between MSM across three regions in Kenya: Coast, Nairobi, and Nyanza. We analyzed 372 HIV-1 partial pol sequences sampled during 2006-2019 from MSM in Coast (N = 178, 47.9%), Nairobi (N = 137, 36.8%), and Nyanza (N = 57, 15.3%) provinces in Kenya. Maximum-likelihood (ML) phylogenetics and Bayesian inference were used to determine HIV-1 clusters, evolutionary dynamics, and virus migration rates between geographic regions. HIV-1 sub-subtype A1 (72.0%) was most common followed by subtype D (11.0%), unique recombinant forms (8.9%), subtype C (5.9%), CRF 21A2D (0.8%), subtype G (0.8%), CRF 16A2D (0.3%), and subtype B (0.3%). Forty-six clusters (size range 2-20 sequences) were found-half (50.0%) of which had evidence of extensive HIV-1 mixing among different provinces. Data revealed an exponential increase in infections among MSM during the early-to-mid 2000s and stable or decreasing transmission dynamics in recent years (2017-2019). Phylogeographic inference showed significant (Bayes factor, BF > 3) HIV-1 dissemination from Coast to Nairobi and Nyanza provinces, and from Nairobi to Nyanza province. Strengthening HIV-1 prevention programs to MSM in geographic locations with higher HIV-1 prevalence among MSM (such as Coast and Nairobi) may reduce HIV-1 incidence among MSM in Kenya.

Quantifying rates of HIV-1 flow between risk groups and geographic locations in Kenya: A country-wide phylogenetic study.

In Kenya, HIV-1 key populations including men having sex with men (MSM), people who inject drugs (PWID) and female sex workers (FSW) are thought to significantly contribute to HIV-1 transmission in the wider, mostly heterosexual (HET) HIV-1 transmission network. However, clear data on HIV-1 transmission dynamics within and between these groups are limited. We aimed to empirically quantify rates of HIV-1 flow between key populations and the HET population, as well as between different geographic regions to determine HIV-1 'hotspots' and their contribution to HIV-1 transmission in Kenya. We used maximum-likelihood phylogenetic and Bayesian inference to analyse 4058 HIV-1 pol sequences (representing 0.3 per cent of the epidemic in Kenya) sampled 1986-2019 from individuals of different risk groups and regions in Kenya. We found 89 per cent within-risk group transmission and 11 per cent mixing between risk groups, cyclic HIV-1 exchange between adjoining geographic provinces and strong evidence of HIV-1 dissemination from (i) West-to-East (i.e. higher-to-lower HIV-1 prevalence regions), and (ii) heterosexual-to-key populations. Low HIV-1 prevalence regions and key populations are sinks rather than major sources of HIV-1 transmission in Kenya. Targeting key populations in Kenya needs to occur concurrently with strengthening interventions in the general epidemic.

TRIM22 genotype is not associated with markers of disease progression in children with HIV-1 infection.

OBJECTIVE: Untreated perinatal HIV-1 infection is often associated with rapid disease progression in children with HIV (CWH), characterized by high viral loads and early mortality. TRIM22 is a host restriction factor, which directly inhibits HIV-1 transcription, and its genotype variation is associated with disease progression in adults. We tested the hypothesis that TRIM22 genotype is associated with disease progression in CWH. DESIGN: ART-naive CWH, aged 6-16 years, were recruited from primary care clinics in Harare, Zimbabwe. We performed a candidate gene association study of TRIM22 genotype and haplotypes with markers of disease progression and indicators of advanced disease. METHODS: TRIM22 exons three and four were sequenced by Sanger sequencing and single nucleotide polymorphisms were associated with markers of disease progression (CD4+ T-cell count and HIV viral load) and clinical indicators of advanced HIV disease (presence of stunting and chronic diarrhoea). Associations were tested using multivariate linear and logistic regression models. RESULTS: A total of 241 children, median age 11.4 years, 50% female, were included. Stunting was present in 16% of participants. Five SNPs were analyzed including rs7935564, rs2291842, rs78484876, rs1063303 and rs61735273. The median CD4+ count was 342 (IQR: 195-533) cells/µl and median HIV-1 viral load 34 199 (IQR: 8211-90 662) IU/ml. TRIM22 genotype and haplotypes were not associated with CD4+ T-cell count, HIV-1 viral load, stunting or chronic diarrhoea. CONCLUSION: TRIM22 genotype was not associated with markers of HIV disease progression markers or advanced disease in CWH.

Inverted CD8 T-Cell Exhaustion and Co-Stimulation Marker Balance Differentiate Aviremic HIV-2-Infected From Seronegative Individuals.

HIV-2 is less pathogenic compared to HIV-1. Still, disease progression may develop in aviremic HIV-2 infection, but the driving forces and mechanisms behind such development are unclear. Here, we aimed to reveal the immunophenotypic pattern associated with CD8 T-cell pathology in HIV-2 infection, in relation to viremia and markers of disease progression. The relationships between pathological differences of the CD8 T-cell memory population and viremia were analyzed in blood samples obtained from an occupational cohort in Guinea-Bissau, including HIV-2 viremic and aviremic individuals. For comparison, samples from HIV-1- or dually HIV-1/2-infected and seronegative individuals were obtained from the same cohort. CD8 T-cell exhaustion was evaluated by the combined expression patterns of activation, stimulatory and inhibitory immune checkpoint markers analyzed using multicolor flow cytometry and advanced bioinformatics. Unsupervised multidimensional clustering analysis identified a cluster of late differentiated CD8 T-cells expressing activation (CD38+, HLA-DRint/high), co-stimulatory (CD226+/-), and immune inhibitory (2B4+, PD-1high, TIGIThigh) markers that distinguished aviremic from viremic HIV-2, and treated from untreated HIV-1-infected individuals. This CD8 T-cell population displayed close correlations to CD4%, viremia, and plasma levels of IP-10, sCD14 and beta-2 microglobulin in HIV-2 infection. Detailed analysis revealed that aviremic HIV-2-infected individuals had higher frequencies of exhausted TIGIT+ CD8 T-cell populations lacking CD226, while reduced percentage of stimulation-receptive TIGIT-CD226+ CD8 T-cells, compared to seronegative individuals. Our results suggest that HIV-2 infection, independent of viremia, skews CD8 T-cells towards exhaustion and reduced co-stimulation readiness. Further knowledge on CD8 T-cell phenotypes might provide help in therapy monitoring and identification of immunotherapy targets.

Phylogenetic and Drug-Resistance Analysis of HIV-1 Sequences From an Extensive Paediatric HIV-1 Outbreak in Larkana, Pakistan.

INTRODUCTION: In April 2019, an HIV-1 outbreak among children occurred in Larkana, Pakistan, affecting more than a thousand children. It was assumed that the outbreak originated from a single source, namely a doctor at a private health facility. In this study, we performed subtype distribution, phylogenetic and drug-resistance analysis of HIV-1 sequences from 2019 outbreak in Larkana, Pakistan. METHODS: A total of 401 blood samples were collected between April-June 2019, from children infected with HIV-1 aged 0-15 years recruited into a case-control study to investigate the risk factors for HIV-1 transmission. Partial HIV-1 pol sequences were generated from 344 blood plasma samples to determine HIV-1 subtype and drug resistance mutations (DRM). Maximum-likelihood phylogenetics based on outbreak and reference sequences was used to identify transmission clusters and assess the relationship between outbreak and key population sequences between and within the determined clusters. Bayesian analysis was employed to identify the time to the most recent common recent ancestor (tMRCA) of the main Pakistani clusters. RESULTS: The HIV-1 circulating recombinant form (CRF) 02_AG and subtype A1 were most common among the outbreak sequences. Of the treatment-naïve participants, the two most common mutations were RT: E138A (8%) and RT: K219Q (8%). Four supported clusters within the outbreak were identified, and the median tMRCAs of the Larkana outbreak sequences were estimated to 2016 for both the CRF02_AG and the subtype A1 clusters. Furthermore, outbreak sequences exhibited no phylogenetic mixing with sequences from other high-risk groups of Pakistan. CONCLUSION: The presence of multiple clusters indicated a multi-source outbreak, rather than a single source outbreak from a single health practitioner as previously suggested. The multiple introductions were likely a consequence of ongoing transmission within the high-risk groups of Larkana, and it is possible that the so-called Larkana strain was introduced into the general population through poor infection prevention control practices in healthcare settings. The study highlights the need to scale up HIV-1 prevention programmes among key population groups and improving infection prevention control in Pakistan.

The Role of Phylogenetics in Discerning HIV-1 Mixing among Vulnerable Populations and Geographic Regions in Sub-Saharan Africa: A Systematic Review.

To reduce global HIV-1 incidence, there is a need to understand and disentangle HIV-1 transmission dynamics and to determine the geographic areas and populations that act as hubs or drivers of HIV-1 spread. In Sub-Saharan Africa (sSA), the region with the highest HIV-1 burden, information about such transmission dynamics is sparse. Phylogenetic inference is a powerful method for the study of HIV-1 transmission networks and source attribution. In this review, we assessed available phylogenetic data on mixing between HIV-1 hotspots (geographic areas and populations with high HIV-1 incidence and prevalence) and areas or populations with lower HIV-1 burden in sSA. We searched PubMed and identified and reviewed 64 studies on HIV-1 transmission dynamics within and between risk groups and geographic locations in sSA (published 1995-2021). We describe HIV-1 transmission from both a geographic and a risk group perspective in sSA. Finally, we discuss the challenges facing phylogenetic inference in mixed epidemics in sSA and offer our perspectives and potential solutions to the identified challenges.

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.

The HIV care continuum and HIV-1 drug resistance among female sex workers: a key population in Guinea-Bissau.

INTRODUCTION: Female sex workers (FSW) are considered a key group for HIV transmissions in sub-Saharan Africa. The HIV Care Continuum and HIV drug resistance (HIVDR) among FSW has not been well studied in most countries in West Africa. In the current study we describe the HIV Care continuum and prevalence of HIVDR among FSW in Guinea-Bissau. METHODS: A venue-based recruitment and peer-referral of FSW was used in seven cities in Guinea-Bissau from October 2014 to September 2017. We administered a questionnaire, performed discriminatory HIV-testing and collected blood specimens for CD4 count, viral load and HIVDR genotyping. RESULTS: The survey included 440 FSW. The overall HIV-prevalence among FSW was 26.8%. Of the HIV-1 (HIV-1 single- or dually HIV-1/HIV-2) infected FSW (N = 104), 58.7% were previously diagnosed with HIV-1 at enrolment and 41.4% reported taking antiretroviral therapy (ART) compared to 28.6% of the HIV-2 single-infected FSW (N = 14). Among HIV-1 infected FSW on ART (N = 43), 55.8% were virally suppressed (< 1000 copies/ml) and of all HIV-1 infected FSW, 29.8% were virally suppressed. Among ART experienced FSW (N = 22), 50.0% had HIVDR. HIVDR was also found in 9.4% of treatment naïve FSW (N = 53). CONCLUSION: The majority of FSW who knew their HIV status received ART, however a large proportion of FSW were not aware of their HIV positive status. This translated into a great majority of the HIV-infected FSW not being virally suppressed. Amongst treatment naïve FSW nearly a tenth had HIVDR, suggesting that sexual transmission of HIVDR is occurring in this at-risk-population.

HIV-1 Transmission Patterns Within and Between Risk Groups in Coastal Kenya.

HIV-1 transmission patterns within and between populations at different risk of HIV-1 acquisition in Kenya are not well understood. We investigated HIV-1 transmission networks in men who have sex with men (MSM), injecting drug users (IDU), female sex workers (FSW) and heterosexuals (HET) in coastal Kenya. We used maximum-likelihood and Bayesian phylogenetics to analyse new (N = 163) and previously published (N = 495) HIV-1 polymerase sequences collected during 2005-2019. Of the 658 sequences, 131 (20%) were from MSM, 58 (9%) IDU, 109 (17%) FSW, and 360 (55%) HET. Overall, 206 (31%) sequences formed 61 clusters. Most clusters (85%) consisted of sequences from the same risk group, suggesting frequent within-group transmission. The remaining clusters were mixed between HET/MSM (7%), HET/FSW (5%), and MSM/FSW (3%) sequences. One large IDU-exclusive cluster was found, indicating an independent sub-epidemic among this group. Phylodynamic analysis of this cluster revealed a steady increase in HIV-1 infections among IDU since the estimated origin of the cluster in 1987. Our results suggest mixing between high-risk groups and heterosexual populations and could be relevant for the development of targeted HIV-1 prevention programmes in coastal Kenya.

Characterisation of HIV-1 Molecular Epidemiology in Nigeria: Origin, Diversity, Demography and Geographic Spread.

Nigeria has the highest number of AIDS-related deaths in the world. In this study, we characterised the HIV-1 molecular epidemiology by analysing 1442 HIV-1 pol sequences collected 1999-2014 from four geopolitical zones in Nigeria using state-of-the-art maximum-likelihood and Bayesian phylogenetic analyses. The main circulating forms were the circulating recombinant form (CRF) 02_AG (44% of the analysed sequences), CRF43_02G (16%), and subtype G (8%). Twenty-three percent of the sequences represented unique recombinant forms (URFs), whereof 37 (11%) could be grouped into seven potentially novel CRFs. Bayesian phylodynamic analysis suggested that five major Nigerian HIV-1 sub-epidemics were introduced in the 1960s and 1970s, close to the Nigerian Civil War. The analysis also indicated that the number of effective infections decreased in Nigeria after the introduction of free antiretroviral treatment in 2006. Finally, Bayesian phylogeographic analysis suggested gravity-like dynamics in which virus lineages first emerge and expand within large urban centers such as Abuja and Lagos, before migrating towards smaller rural areas. This study provides novel insight into the Nigerian HIV-1 epidemic and may have implications for future HIV-1 prevention strategies in Nigeria and other severely affected countries.

HIV-2 as a model to identify a functional HIV cure.

Two HIV virus types exist: HIV-1 is pandemic and aggressive, whereas HIV-2 is confined mainly to West Africa and less pathogenic. Despite the fact that it has been almost 40 years since the discovery of AIDS, there is still no cure or vaccine against HIV. Consequently, the concepts of functional vaccines and cures that aim to limit HIV disease progression and spread by persistent control of viral replication without life-long treatment have been suggested as more feasible options to control the HIV pandemic. To identify virus-host mechanisms that could be targeted for functional cure development, researchers have focused on a small fraction of HIV-1 infected individuals that control their infection spontaneously, so-called elite controllers. However, these efforts have not been able to unravel the key mechanisms of the infection control. This is partly due to lack in statistical power since only 0.15% of HIV-1 infected individuals are natural elite controllers. The proportion of long-term viral control is larger in HIV-2 infection compared with HIV-1 infection. We therefore present the idea of using HIV-2 as a model for finding a functional cure against HIV. Understanding the key differences between HIV-1 and HIV-2 infections, and the cross-reactive effects in HIV-1/HIV-2 dual-infection could provide novel insights in developing functional HIV cures and vaccines.

T-cell and B-cell perturbations are similar in ART-naive HIV-1 and HIV-1/2 dually infected patients.

BACKGROUND: HIV-2 may slow progression of a subsequently acquired HIV-1 infection through cross-neutralizing antibodies and polyfunctional CD8 T cells. We hypothesized that HIV-1/2 dually infected patients compared with HIV-1-infected patients had more preserved immune maturation subsets and less immune activation of T and B cells. METHODS: ART-naive patients with HIV-1 (n = 83) or HIV-1/2 dual (n = 27) infections were included in this cross-sectional study at an HIV clinic in Guinea-Bissau. Peripheral blood mononuclear cells (PBMCs) were analyzed by flow cytometry according to T-cell maturation and activation, regulatory T-cell fraction, and B-cell maturation and activation. RESULTS: HIV-1/2 dually infected patients had lower levels of HIV-1 RNA compared with patients with HIV-1 infection, but the levels of total HIV RNA (HIV-1 and HIV-2) were similar in the two patient groups. T-cell maturation, and proportions of regulatory T cells (FoxP3+) were also similar in the two groups. HIV-1/2 dually infected patients had higher proportions of CD4 and CD8 T cells positive for the activation marker CD38, but there was no difference in other T-cell activation markers (CD28, CTLA-4, PD-1). HIV-1/2 dually infected patients also had higher proportions of IgM-only B cells and plasmablasts. CONCLUSION: HIV-1/2 was not associated with less immune perturbations than for HIV-1 infection.