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.

Evolution during primary HIV infection does not require adaptive immune selection.

Modern HIV research depends crucially on both viral sequencing and population measurements. To directly link mechanistic biological processes and evolutionary dynamics during HIV infection, we developed multiple within-host phylodynamic models of HIV primary infection for comparative validation against viral load and evolutionary dynamics data. The optimal model of primary infection required no positive selection, suggesting that the host adaptive immune system reduces viral load but surprisingly does not drive observed viral evolution. Rather, the fitness (infectivity) of mutant variants is drawn from an exponential distribution in which most variants are slightly less infectious than their parents (nearly neutral evolution). This distribution was not largely different from either in vivo fitness distributions recorded beyond primary infection or in vitro distributions that are observed without adaptive immunity, suggesting the intrinsic viral fitness distribution may drive evolution. Simulated phylogenetic trees also agree with independent data and illuminate how phylogenetic inference must consider viral and immune-cell population dynamics to gain accurate mechanistic insights.

SARS-CoV-2 antibody prevalence, correlates, and access to harm reduction services among people who inject drugs living with and without HIV and their partners in Kenya.

BACKGROUND: In sub-Saharan Africa many people who inject drugs (PWID) are living with undiagnosed or untreated HIV and experience high levels of poverty and conditions that can contribute to worse outcomes from SARS-CoV-2 infection. Identifying the burden of SARS-CoV-2 infection in marginalized populations like PWID may contribute to controlling the pandemic. METHODS: This is a nested cross-sectional study within an ongoing cohort study that recruits PWID living with HIV and their injecting and/or sexual partners at needle and syringe program sites and methadone clinics in Kenya. Blood samples were collected from consenting participants at enrollment to determine SARS-CoV-2 antibodies using a Platellia BioRad SARS-CoV-2 total antibody enzyme-linked immunosorbent assay. Baseline data were collected on HIV status, antiretroviral therapy and methadone adherence. We used logistic regression to identify factors associated with antibody positivity and descriptive statistics to report SARS-CoV-2 antibody prevalence. RESULTS: One thousand participants were enrolled between April and July 2021, of whom 323 (32.3%) were women and 677 (67.7%) were men. Median age of participants was 36 years (interquartile range: 30, 42). SARS-CoV-2 antibody positivity was found in 309 (30.9%) participants. Disruption in obtaining methadone service was reported by 106 (24.3%) of the participants. Men were significantly less likely than women to have SARS-CoV-2 antibodies (adjusted odds ratio [aOR] = 0.68, 95% confidence interval [CI] 0.51, 0.95; p < 0.01) Participants who reported a sexual or injecting partner diagnosed with SARS-CoV-2 were twofold more likely to have SARS-CoV-2 antibodies detected (aOR = 2.21, 95% CI 1.06, 4.58; p < 0.032). Living with HIV was not associated with presence of SARS-CoV-2 antibodies. CONCLUSION: The seroprevalence of SARS-CoV-2 of 30.9% in this cohort suggests high transmission rates within this population. SARS-CoV-2 seroprevalence was similar for people living with and without HIV. A large portion of this population was noted to have had disruption in access to harm reduction services.

Prevalence and correlates of violence among sexual and injecting partners of people who inject drugs living with HIV in Kenya: a cross-sectional study.

BACKGROUND: In Kenya, violence is common among people who inject drugs (PWID) living with HIV and their sexual and injecting partners and may lead to decreased uptake of HIV services, increased HIV risk behaviors, and increased HIV transmission. Violence is defined as any physical harm, threatened harm, or forced sexual acts inflicted on a person in the past year. Understanding the nature of violence and its correlates among PWID and their partners will inform population-specific public health interventions and policy recommendations. METHODS: This is a cross-sectional study nested in a prospective cohort study conducted in eight public health centers, methadone clinics, and needle syringe programs in Nairobi, Kilifi, and Mombasa counties in Kenya. 3,302 sexual and/or injecting partners of PWID living with HIV were recruited through assisted partner services and participated in the study. Prevalence and correlates of violence were identified using the Wald test and negative binomial regression. RESULTS: Out of 3302 study participants, 1439 (44%) had experienced violence within the past year. Physical violence was the most common form of violence experienced (35%), followed by being threatened (23%) or subjected to sexual violence (7%). In an adjusted analysis, female participants reported higher experiences of sexual violence (prevalence ratio [PR] = 2.46; 95% confidence interval [CI] 1.62, 3.74; p < 0.001) compared to male participants. In adjusted analysis, coastal residents had a higher experience of overall violence (PR = 1.48; 95% CI 1.27, 1.72; p < 0.001) than those living in Nairobi. This regional effect was relatively stronger among the female respondents (pinteraction = 0.025). Participants' sex modified the association between region and experiencing violence after adjusting potential confounding factors. CONCLUSIONS: The study reveals the prevalence of violence among PWID and identifies high-risk sub-groups, including women, specifically for sexual violence, and coastal residents. Tailored interventions addressing their unique needs are essential. A holistic approach that combines violence prevention and response, comprehensive harm reduction, healthcare access, and community support is crucial to address the complex issue of drug use and HIV burden among PWID in Kenya for improved health outcomes.

Molecular Epidemiology of Individuals Experiencing Unstable Housing or Living Homeless at HIV Diagnosis: Analysis of HIV Surveillance Data in King County, Washington.

We examined patterns of genetic clustering among individuals diagnosed with HIV between 2010 and 2018 using data from King County, Washington's National HIV Surveillance System. Among 2,371 individuals newly diagnosed with HIV, 231 (10%) experienced unstable housing or were living homeless at the time of diagnosis. Among the 1,658 (70%) people with an available HIV-1 pol gene sequence, 1,071 (65%) were identified to be part of 296 genetic clusters. In our analysis, housing status was not associated with genetic clustering (OR 1.02; 95%CI:0.75,1.39). After adjusting for demographic and behavioral factors, people who were living homeless at HIV diagnosis had 35% lower odds of being identified as part of a genetic cluster (AOR 0.65; 95%CI:0.44,0.95) compared to people with stable housing. Our findings highlight that people experiencing unstable housing are disproportionately burdened by HIV, and that within this population in King County, being in a genetic cluster is predominantly associated with substance use.

Characteristics associated with HIV and hepatitis C seroprevalence among sexual and injecting partners of HIV positive persons who inject drugs in Nairobi and coastal Kenya.

BACKGROUND: Persons who inject drugs (PWID) have higher HIV and hepatitis C virus (HCV) seroprevalence than the general population in many parts of sub-Saharan Africa (SSA). The seroprevalences of HIV and HCV are also higher in coastal Kenya than in Nairobi. Understanding drivers of regional HIV and HCV variation among PWID in Kenya may inform population-specific prevention interventions. METHODS: Using a cross-sectional study, we defined HIV and HCV seroprevalence among persons identified as sexual or injecting partners of HIV positive PWID in two regions of Kenya and used logistic regression to identify demographic and behavioral characteristics associated with higher seroprevalence. RESULTS: Among 2386 partners, 469 (19.7%) tested HIV positive and 297(12.4%) tested HCV antibody positive. Partners on the Coast were more likely to live with HIV (seroprevalences: Coast = 23.8%, Nairobi = 17.1%; p < 0.001) and be HCV antibody positive (seroprevalences: Coast = 17.0%, Nairobi = 8.6%; p < 0.001). After adjusting for sex, age, and years injecting and accounting for clustering by site, the higher prevalence of both diseases in the Coast remained significant for HIV (OR 1.68, 95% CI 1.13-2.51) but not for HCV (OR 1.72, 95% CI 0.84-3.74). Compared to those recruited in Nairobi, partners on the Coast were older (Coast = 35 years, Nairobi = 31 years; p < 0.001), more likely to be male (Coast = 77.6%, Nairobi = 61.7%; p < 0.001), to have paid (Coast = 59.2%, Nairobi = 32.8%; p < 0.001) or received (Coast = 44.2%, Nairobi 35.4%; p < 0.001) money for sex, or to have had sex with someone they knew to be HIV positive (Coast 22.0%, Nairobi 10.8%; p < 0.001). Partners who had injected for five or more years had 1.48 times greater odds (95% CI 1.20-1.82) of living with HIV compared to partners who injected less than 5 years and more than twice the odds of HCV (95% CI 1.84-4.11). CONCLUSION: HIV and HCV seroprevalence among sexual and injecting partners of PWID was, respectively, 5 times and > 12 times greater than is reported among the general population in Kenya (4% and < 1%, respectively). Providing resources and education will be crucial to reduce exposure and to maintain the lower needle and equipment sharing that we observed compared to other studies.

Large benefits to youth-focused HIV treatment-as-prevention efforts in generalized heterosexual populations: An agent-based simulation model.

Predominantly heterosexual HIV-1 epidemics like those in sub-Saharan Africa continue to have high HIV incidence in young people. We used a stochastic, agent-based model for age-disparate networks to test the hypothesis that focusing uptake and retention of ART among youth could enhance the efficiency of treatment as prevention (TasP) campaigns. We used the model to identify strategies that reduce incidence to negligible levels (i.e., < 0.1 cases/100 person-years) 20-25 years after initiation of a targeted TasP campaign. The model was parameterized using behavioral, demographic, and clinical data from published papers and national reports. To keep a focus on the underlying age effects we model a generalized heterosexual population with average risks (i.e., no MSM, no PWIDs, no sex workers) and no entry of HIV+ people from other regions. The model assumes that most people (default 95%, range in variant simulations 60-95%) are "linkable"; i.e., could get linked to effective care given sufficient resources. To simplify the accounting, we assume a rapid jump in the number of people receiving treatment at the start of the TasP campaign, followed by a 2% annual increase that continues until all linkable HIV+ people have been treated. Under historical scenarios of CD4-based targeted ART allocation and current policies of untargeted (random) ART allocation, our model predicts that viral replication would need to be suppressed in 60-85% of infected people at the start of the TasP campaign to drive incidence to negligible levels. Under age-based strategies, by contrast, this percentage dropped by 18-54%, depending on the strength of the epidemic and the age target. For our baseline model, targeting those under age 30 halved the number of people who need to be treated. Age-based targeting also minimized total and time-discounted AIDS deaths over 25 years. Age-based targeting yielded benefits without being highly exclusive; in a model in which 60% of infected people were treated, ~87% and ~58% of those initiating therapy during a campaign targeting those <25 and <30 years, respectively, fell outside the target group. Sensitivity analyses revealed that youth-focused TasP is beneficial due to age-related risk factors (e.g. shorter relationship durations), and an age-specific herd immunity (ASHI) effect that protects uninfected adolescents entering the sexually active population. As testing rates increase in response to UNAIDS 90-90-90 goals, efforts to link all young people to care and treatment could contribute enormously to ending the HIV epidemic.

Genetic Cluster Analysis for HIV Prevention.

PURPOSE OF REVIEW: This review summarizes the use of genetic similarity clusters to understand HIV transmission and inform prevention efforts. RECENT FINDINGS: Recent emphases include the development of real-time cluster identification in order to interrupt transmission chains, the use of clusters to estimate rates of transmission along the HIV care cascade, and the extension of cluster analyses to understand transmission in the generalized epidemics of sub-Saharan Africa. Importantly, this recent empirical work has been accompanied by theoretical work that elucidates the processes that underlie HIV genetic similarity clusters; multiple studies suggest that clusters are not necessarily enriched with individuals with high transmission rates, but rather can reflect variation in sampling times within a population, with individuals sampled early in infection more likely to cluster. Analyses of genetic similarity clusters have great promise to inform HIV epidemiology and prevention. Future emphases should include the collection of additional sequence data from underrepresented populations, such as those in sub-Saharan Africa, and further development and evaluation of clustering methods.

Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load.

Previous genome-wide association studies (GWAS) of HIV-1-infected populations have been underpowered to detect common variants with moderate impact on disease outcome and have not assessed the phenotypic variance explained by genome-wide additive effects. By combining the majority of available genome-wide genotyping data in HIV-infected populations, we tested for association between ∼8 million variants and viral load (HIV RNA copies per milliliter of plasma) in 6,315 individuals of European ancestry. The strongest signal of association was observed in the HLA class I region that was fully explained by independent effects mapping to five variable amino acid positions in the peptide binding grooves of the HLA-B and HLA-A proteins. We observed a second genome-wide significant association signal in the chemokine (C-C motif) receptor (CCR) gene cluster on chromosome 3. Conditional analysis showed that this signal could not be fully attributed to the known protective CCR5Δ32 allele and the risk P1 haplotype, suggesting further causal variants in this region. Heritability analysis demonstrated that common human genetic variation-mostly in the HLA and CCR5 regions-explains 25% of the variability in viral load. This study suggests that analyses in non-European populations and of variant classes not assessed by GWAS should be priorities for the field going forward.

Association study of common genetic variants and HIV-1 acquisition in 6,300 infected cases and 7,200 controls.

Multiple genome-wide association studies (GWAS) have been performed in HIV-1 infected individuals, identifying common genetic influences on viral control and disease course. Similarly, common genetic correlates of acquisition of HIV-1 after exposure have been interrogated using GWAS, although in generally small samples. Under the auspices of the International Collaboration for the Genomics of HIV, we have combined the genome-wide single nucleotide polymorphism (SNP) data collected by 25 cohorts, studies, or institutions on HIV-1 infected individuals and compared them to carefully matched population-level data sets (a list of all collaborators appears in Note S1 in Text S1). After imputation using the 1,000 Genomes Project reference panel, we tested approximately 8 million common DNA variants (SNPs and indels) for association with HIV-1 acquisition in 6,334 infected patients and 7,247 population samples of European ancestry. Initial association testing identified the SNP rs4418214, the C allele of which is known to tag the HLA-B*57:01 and B*27:05 alleles, as genome-wide significant (p = 3.6 × 10⁻¹¹). However, restricting analysis to individuals with a known date of seroconversion suggested that this association was due to the frailty bias in studies of lethal diseases. Further analyses including testing recessive genetic models, testing for bulk effects of non-genome-wide significant variants, stratifying by sexual or parenteral transmission risk and testing previously reported associations showed no evidence for genetic influence on HIV-1 acquisition (with the exception of CCR5Δ32 homozygosity). Thus, these data suggest that genetic influences on HIV acquisition are either rare or have smaller effects than can be detected by this sample size.

An HIV epidemic model based on viral load dynamics: value in assessing empirical trends in HIV virulence and community viral load.

Trends in HIV virulence have been monitored since the start of the AIDS pandemic, as studying HIV virulence informs our understanding of HIV epidemiology and pathogenesis. Here, we model changes in HIV virulence as a strictly evolutionary process, using set point viral load (SPVL) as a proxy, to make inferences about empirical SPVL trends from longitudinal HIV cohorts. We develop an agent-based epidemic model based on HIV viral load dynamics. The model contains functions for viral load and transmission, SPVL and disease progression, viral load trajectories in multiple stages of infection, and the heritability of SPVL across transmissions. We find that HIV virulence evolves to an intermediate level that balances infectiousness with longer infected lifespans, resulting in an optimal SPVL∼4.75 log10 viral RNA copies/mL. Adaptive viral evolution may explain observed HIV virulence trends: our model produces SPVL trends with magnitudes that are broadly similar to empirical trends. With regard to variation among studies in empirical SPVL trends, results from our model suggest that variation may be explained by the specific epidemic context, e.g. the mean SPVL of the founding lineage or the age of the epidemic; or improvements in HIV screening and diagnosis that results in sampling biases. We also use our model to examine trends in community viral load, a population-level measure of HIV viral load that is thought to reflect a population's overall transmission potential. We find that community viral load evolves in association with SPVL, in the absence of prevention programs such as antiretroviral therapy, and that the mean community viral load is not necessarily a strong predictor of HIV incidence.

Virologic Nonsuppression and HIV Drug Resistance Among People Who Inject Drugs and Their Sexual and Injecting Partners in Kenya.

We evaluated the prevalence and correlates of HIV viral nonsuppression and HIV drug resistance (HIV-DR) in a cohort of people who inject drugs living with HIV (PWID-LH) and their sexual and injecting partners living with HIV in Kenya. HIV-DR testing was performed on participants with viral nonsuppression. Of 859 PWID-LH and their partners, 623 (72.5%) were on antiretroviral therapy (ART) ≥4 months and 148/623 (23.8%) were not virally suppressed. Viral nonsuppression was more common among younger participants and those on ART for a shorter duration. Among 122/148 (82.4%) successfully sequenced samples, 55 (45.1%) had detectable major HIV-DR mutations, mainly to non-nucleoside and nucleotide reverse transcriptase inhibitors (NNRTI and NRTI). High levels of HIV-DR among those with viral nonsuppression suggests need for viral load monitoring, adherence counseling, and timely switching to alternate ART regimens in this key population.

Increasing intra- and inter-subtype HIV diversity despite declining HIV incidence in Uganda.

HIV incidence has been declining in Africa with scale-up of HIV interventions. However, there is limited data on HIV evolutionary trends in African populations with waning epidemics. We evaluated changes in HIV viral diversity and genetic divergence in southern Uganda over a twenty-five-year period spanning the introduction and scale-up of HIV prevention and treatment programs using HIV sequence and survey data from the Rakai Community Cohort Study, an open longitudinal population-based HIV surveillance cohort. Gag (p24) and env (gp41) HIV data were generated from persons living with HIV (PLHIV) in 31 inland semi-urban trading and agrarian communities (1994 to 2018) and four hyperendemic Lake Victoria fishing communities (2011 to 2018) under continuous surveillance. HIV subtype was assigned using the Recombination Identification Program with phylogenetic confirmation. Inter-subtype diversity was estimated using the Shannon diversity index and intra-subtype diversity with the nucleotide diversity and pairwise TN93 genetic distance. Genetic divergence was measured using root-to-tip distance and pairwise TN93 genetic distance analyses. Evolutionary dynamics were assessed among demographic and behavioral sub-groups, including by migration status. 9,931 HIV sequences were available from 4,999 PLHIV, including 3,060 and 1,939 persons residing in inland and fishing communities, respectively. In inland communities, subtype A1 viruses proportionately increased from 14.3% in 1995 to 25.9% in 2017 (p<0.001), while those of subtype D declined from 73.2% in 1995 to 28.2% in 2017 (p<0.001). The proportion of viruses classified as recombinants significantly increased by more than four-fold. Inter-subtype HIV diversity has generally increased. While p24 intra-subtype genetic diversity and divergence leveled off after 2014, diversity and divergence of gp41 increased through 2017. Inter- and intra-subtype viral diversity increased across all population sub-groups, including among individuals with no recent migration history or extra-community sexual partners. This study provides insights into population-level HIV evolutionary dynamics in declining African HIV epidemics following the scale-up of HIV prevention and treatment programs. Continued molecular surveillance may provide a better understanding of the dynamics driving population HIV evolution and yield important insights for epidemic control and vaccine development.

Intra- and inter-subtype HIV diversity between 1994 and 2018 in southern Uganda: a longitudinal population-based study.

There is limited data on human immunodeficiency virus (HIV) evolutionary trends in African populations. We evaluated changes in HIV viral diversity and genetic divergence in southern Uganda over a 24-year period spanning the introduction and scale-up of HIV prevention and treatment programs using HIV sequence and survey data from the Rakai Community Cohort Study, an open longitudinal population-based HIV surveillance cohort. Gag (p24) and env (gp41) HIV data were generated from people living with HIV (PLHIV) in 31 inland semi-urban trading and agrarian communities (1994-2018) and four hyperendemic Lake Victoria fishing communities (2011-2018) under continuous surveillance. HIV subtype was assigned using the Recombination Identification Program with phylogenetic confirmation. Inter-subtype diversity was evaluated using the Shannon diversity index, and intra-subtype diversity with the nucleotide diversity and pairwise TN93 genetic distance. Genetic divergence was measured using root-to-tip distance and pairwise TN93 genetic distance analyses. Demographic history of HIV was inferred using a coalescent-based Bayesian Skygrid model. Evolutionary dynamics were assessed among demographic and behavioral population subgroups, including by migration status. 9931 HIV sequences were available from 4999 PLHIV, including 3060 and 1939 persons residing in inland and fishing communities, respectively. In inland communities, subtype A1 viruses proportionately increased from 14.3% in 1995 to 25.9% in 2017 (P < .001), while those of subtype D declined from 73.2% in 1995 to 28.2% in 2017 (P < .001). The proportion of viruses classified as recombinants significantly increased by nearly four-fold from 12.2% in 1995 to 44.8% in 2017. Inter-subtype HIV diversity has generally increased. While intra-subtype p24 genetic diversity and divergence leveled off after 2014, intra-subtype gp41 diversity, effective population size, and divergence increased through 2017. Intra- and inter-subtype viral diversity increased across all demographic and behavioral population subgroups, including among individuals with no recent migration history or extra-community sexual partners. This study provides insights into population-level HIV evolutionary dynamics following the scale-up of HIV prevention and treatment programs. Continued molecular surveillance may provide a better understanding of the dynamics driving population HIV evolution and yield important insights for epidemic control and vaccine development.

CD39/adenosine pathway is involved in AIDS progression.

HIV-1 infection is characterized by a chronic activation of the immune system and suppressed function of T lymphocytes. Regulatory CD4+ CD25(high) FoxP3+CD127(low) T cells (Treg) play a key role in both conditions. Here, we show that HIV-1 positive patients have a significant increase of Treg-associated expression of CD39/ENTPD1, an ectoenzyme which in concert with CD73 generates adenosine. We show in vitro that the CD39/adenosine axis is involved in Treg suppression in HIV infection. Treg inhibitory effects are relieved by CD39 down modulation and are reproduced by an adenosine-agonist in accordance with a higher expression of the adenosine A2A receptor on patients' T cells. Notably, the expansion of the Treg CD39+ correlates with the level of immune activation and lower CD4+ counts in HIV-1 infected patients. Finally, in a genetic association study performed in three different cohorts, we identified a CD39 gene polymorphism that was associated with down-modulated CD39 expression and a slower progression to AIDS.

Lessons learned from community engagement regarding phylodynamic research with molecular HIV surveillance data.

INTRODUCTION: The widespread implementation of molecular HIV surveillance (MHS) has resulted in an increased discussion about the ethical, human rights and public health implications of MHS. We narrate our process of pausing our research that uses data collected through MHS in response to these growing concerns and summarize the key lessons we learned through conversations with community members. METHODS: The original study aimed to describe HIV transmission patterns by age and race/ethnicity among men who have sex with men in King County, Washington, by applying probabilistic phylodynamic modelling methods to HIV-1 pol gene sequences collected through MHS. In September 2020, we paused the publication of this research to conduct community engagement: we held two public-facing online presentations, met with a national community coalition that included representatives of networks of people living with HIV, and invited two members of this coalition to provide feedback on our manuscript. During each of these meetings, we shared a brief presentation of our methods and findings and explicitly solicited feedback on the perceived public health benefit and potential harm of our analyses and results. RESULTS: Some community concerns about MHS in public health practice also apply to research using MHS data, namely those related to informed consent, inference of transmission directionality and criminalization. Other critiques were specific to our research study and included feedback about the use of phylogenetic analyses to study assortativity by race/ethnicity and the importance of considering the broader context of stigma and structural racism. We ultimately decided the potential harms of publishing our study-perpetuating racialized stigma about men who have sex with men and eroding the trust between phylogenetics researchers and communities of people living with HIV-outweighed the potential benefits. CONCLUSIONS: HIV phylogenetics research using data collected through MHS data is a powerful scientific technology with the potential to benefit and harm communities of people living with HIV. Addressing criminalization and including people living with HIV in decision-making processes have the potential to meaningfully address community concerns and strengthen the ethical justification for using MHS data in both research and public health practice. We close with specific opportunities for action and advocacy by researchers.

Evolution of HIV virulence in response to disease-modifying vaccines: A modeling study.

Pathogens face a tradeoff with respect to virulence; while more virulent strains often have higher per-contact transmission rates, they are also more likely to kill their hosts earlier. Because virulence is a heritable trait, there is concern that a disease-modifying vaccine, which reduces the disease severity of an infected vaccinee without changing the underlying pathogen genotype, may result in the evolution of higher pathogen virulence. We explored the potential for such virulence evolution with a disease-modifying HIV-1 vaccine in an agent-based stochastic epidemic model of HIV in United States men who have sex with men (MSM). In the model, vaccinated agents received no protection against infection, but experienced lower viral loads and slower disease progression. We compared the genotypic set point viral load (SPVL), a measure of HIV virulence, in populations given vaccines that varied in the degree of SPVL reduction they induce. Sensitivity analyses were conducted under varying vaccine coverage scenarios. With continual vaccination rollout under ideal circumstances of 90 % coverage over thirty years, the genotypic SPVL of vaccinated individuals evolved to become greater than the genotypic SPVL of unvaccinated individuals. This virulence evolution in turn diminished the public health benefit of the vaccine, and in some scenarios resulted in an accelerated epidemic. These findings demonstrate the complexity of viral evolution and have important implications for the design and development of HIV vaccines.

Demographic processes affect HIV-1 evolution in primary infection before the onset of selective processes.

HIV-1 transmission and viral evolution in the first year of infection were studied in 11 individuals representing four transmitter-recipient pairs and three independent seroconverters. Nine of these individuals were enrolled during acute infection; all were men who have sex with men (MSM) infected with HIV-1 subtype B. A total of 475 nearly full-length HIV-1 genome sequences were generated, representing on average 10 genomes per specimen at 2 to 12 visits over the first year of infection. Single founding variants with nearly homogeneous viral populations were detected in eight of the nine individuals who were enrolled during acute HIV-1 infection. Restriction to a single founder variant was not due to a lack of diversity in the transmitter as homogeneous populations were found in recipients from transmitters with chronic infection. Mutational patterns indicative of rapid viral population growth dominated during the first 5 weeks of infection and included a slight contraction of viral genetic diversity over the first 20 to 40 days. Subsequently, selection dominated, most markedly in env and nef. Mutants were detected in the first week and became consensus as early as day 21 after the onset of symptoms of primary HIV infection. We found multiple indications of cytotoxic T lymphocyte (CTL) escape mutations while reversions appeared limited. Putative escape mutations were often rapidly replaced with mutually exclusive mutations nearby, indicating the existence of a maturational escape process, possibly in adaptation to viral fitness constraints or to immune responses against new variants. We showed that establishment of HIV-1 infection is likely due to a biological mechanism that restricts transmission rather than to early adaptive evolution during acute infection. Furthermore, the diversity of HIV strains coupled with complex and individual-specific patterns of CTL escape did not reveal shared sequence characteristics of acute infection that could be harnessed for vaccine design.

A public health approach to monitoring HIV with resistance to HIV pre-exposure prophylaxis.

BACKGROUND: The risk of HIV pre-exposure prophylaxis (PrEP) failure with sufficient medication adherence is extremely low but has occurred due to transmission of a viral strain with mutations conferring resistance to PrEP components tenofovir (TDF) and emtricitabine (FTC). The extent to which such strains are circulating in the population is unknown. METHODS: We used HIV surveillance data to describe primary and overall TDF/FTC resistance and concurrent viremia among people living with HIV (PLWH). HIV genotypes conducted for clinical purposes are reported as part of HIV surveillance. We examined the prevalence of HIV strains with mutations conferring intermediate to high level resistance to TDF/FTC, defining primary resistance (predominantly K65R and M184I/V mutations) among sequences reported within 3 months of HIV diagnosis and total resistance for sequences reported at any time. We examined trends in primary resistance during 2010-2019 and total resistance among all PLWH in 2019. We also monitored resistance with viremia (≥1,000 copies/mL) at the end of 2019 among PLWH. RESULTS: Between 2010 and 2019, 2,172 King County residents were diagnosed with HIV; 1,557 (72%) had a genotypic resistance test within three months; three (0.2%) had primary TDF/FTC resistance with both K65R and M184I/V mutations. Adding isolated resistance for each drug resulted in 0.3% with primary TDF resistance and 0.8% with primary FTC resistance. Of 7,056 PLWH in 2019, 4,032 (57%) had genotype results, 241 (6%) had TDF/FTC resistance and 15 (0.4% of those with a genotype result) had viremia and TDF/FTC resistance. CONCLUSIONS: Primary resistance and viremia combined with TDF/FTC resistance are uncommon in King County. Monitoring trends in TDF/FTC resistance coupled with interventions to help ensure PLWH achieve and maintain viral suppression may help ensure that PrEP failure remains rare.