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.

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.

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.

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.

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.

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.

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.

Why does age at HIV infection correlate with set point viral load? An evolutionary hypothesis.

BACKGROUND: Set-point viral load (SPVL) correlates with the age at which people acquire HIV. Although immunosenescence may seem like a parsimonious explanation for this, it does not easily explain the observation that the relationship between age and SPVL attenuates when accounting for source partner SPVL. Here we propose an alternative explanation that encompasses this latter finding: that decreasing risk of acquisition with older age generates a selection bottleneck that selects for more virulent strains with age. METHODS: We adapted a previously published model of HIV transmission and evolution (EvoNetHIV), parameterized here for men who have sex with men (MSM). We conducted a series of simulation experiments that vary seven behavioral or clinical parameters that affect exposure risk as people age. We conducted regressions to determine the mean increase in SPVL per 10-year increase in seroconversion age, with and without source SPVL in the model. RESULTS: All runs generated significant relationships between seroconversion age and SPVL when not including source SPVL. All saw attenuated relationships, most to near 0, with source SPVL included. Four of our behavioral measures (relational duration, age-related homophily, coital frequency, and mean age at relationship formation) had clear effects on this relationship, all in the hypothesized direction. Combining multiple forms of behavioral heterogeneity yielded an increase of 0.056 log10 copies/mL SPVL per 10-year increase in seroconversion age, nearly as large as that seen in two empirical studies of age-SPVL correlations in MSM. CONCLUSION: The higher virulence of HIV among those infected later in life may be partly explained by a combination of selective bottlenecks and behavioral heterogeneity by age. Variation in the strength of this effect across populations may be in part due to different behavioral, epidemiological and clinical conditions, and not require assumptions about differences in patterns of immunosenescence among populations.

Assisted Partner Services for People Who Inject Drugs: Index Characteristics Associated With Untreated HIV in Partners.

BACKGROUND: Assisted partner services (APSs) is a feasible, acceptable, and effective strategy that increases uptake of HIV testing; however, it has not been used widely among people who inject drugs (PWID) in Africa to notify sexual and injecting partners of potential exposures to HIV and provide testing services. SETTING: Nairobi, Kilifi, and Mombasa counties in Kenya. METHODS: PWID living with HIV (indexes) were enrolled and asked to provide contact information for sexual and injecting partners who were traced and offered HIV testing. APS efficiency was assessed by the number of indexes needed to interview (NNTI) to find 1 additional partner who was unaware of their HIV status or not on antiretroviral therapy (ART). We defined index participant characteristics associated with greater efficiency, defined as lower NNTIs. RESULTS: Among 783 indexes, the NNTI to identify one partner unaware of their HIV status was 7.1 and to identify one HIV-positive partner not on ART (regardless of status awareness) was 4.1. APS was provided to 977 partners and was more efficient in identifying partners who were not on ART (n = 201) among indexes who were female (NNTI = 2.9 vs. 5.7, P < 0.001), unaware of their HIV status (NNTI = 2.2 vs. 4.2, P = 0.009), not on ART (NNTI = 2.1 vs. 4.9; P < 0.001), not enrolled in a methadone program (NNTI = 3.3 vs. 10.4, P < 0.001), reported injecting <5 years (NNTI = 3.3 vs. 5.0; P = 0.005), or from Nairobi (NNTI = 3.2 vs. 5.6, P < 0.001). CONCLUSION: Scaling up APS among PWID living with HIV with certain characteristics could result in more efficient APS and greater partner engagement in HIV care.

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.

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.

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.

HIV transmission patterns among transgender women, their cisgender male partners, and cisgender MSM in Lima, Peru: A molecular epidemiologic and phylodynamic analysis.

BACKGROUND: Transgender women (TW) in Peru are disproportionately affected by HIV. The role that cisgender men who have sex with TW (MSTW) and their sexual networks play in TW's risk of acquiring HIV is not well understood. We used HIV sequences from TW, MSTW, and cisgender men who have sex with men (MSM) to examine transmission dynamics between these groups. METHODS: We used HIV-1 pol sequences and epidemiologic data collected through three Lima-based studies from 2013 to 2018 (n = 139 TW, n = 25 MSTW, n = 303 MSM). We identified molecular clusters based on pairwise genetic distance and used structured coalescent phylodynamic modeling to estimate transmission patterns between groups. FINDINGS: Among 200 participants (43%) found in 62 clusters, the probability of clustering did not differ by group. Both MSM and TW were more likely to cluster with members of their own group than would be expected based on random mixing. Phylodynamic modeling estimated that there was frequent transmission from MSTW to TW (67·9% of transmission from MSTW; 95%CI = 52·8-83·2%) and from TW to MSTW (76·5% of transmissions from TW; 95%CI = 65·5-90·3%). HIV transmission between MSM and TW was estimated to comprise a small proportion of overall transmissions (4·9% of transmissions from MSM, and 11·8% of transmissions from TW), as were transmissions between MSM and MSTW (7·2% of transmissions from MSM, and 32·0% of transmissions from MSTW). INTERPRETATION: These results provide quantitative evidence that MSTW play an important role in TW's HIV vulnerability and that MSTW have an HIV transmission network that is largely distinct from MSM.

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.

Detection and Response to an HIV Cluster: People Living Homeless and Using Drugs in Seattle, Washington.

INTRODUCTION: The HIV epidemic in King County, Washington has traditionally been highly concentrated among men who have sex with men, and incidence has gradually declined over 2 decades. In 2018, King County experienced a geographically concentrated outbreak of HIV among heterosexual people who inject drugs. METHODS: Data sources to describe the 2018 outbreak and King County's response were partner services interview data, HIV case reports, syringe service program client surveys, hospital data, and data from a rapid needs assessment of homeless individuals and people who inject drugs. In 2020, the authors examined the impact of delays in molecular sequence analyses and cluster member size thresholds, for identifying genetically similar clusters, on the timing of outbreak identification. RESULTS: In 2018, the health department identified a North Seattle cluster, growing to 30 people with related HIV infections diagnosed in 2008-2019. In total, 70% of cluster members were female, 77% were people who inject drugs, 87% were homeless, and 27% reported exchanging sex. Intervention activities included a rapid needs assessment, 2,485 HIV screening tests in a jail and other outreach settings, provision of 87,488 clean syringes in the outbreak area, and public communications. A lower cluster size threshold and more rapid receipt and analyses of data would have identified this outbreak 4-16 months earlier. CONCLUSIONS: This outbreak shows the vulnerability of people who inject drugs to HIV infection, even in areas with robust syringe service programs and declining HIV epidemics. Although molecular HIV surveillance did not identify this outbreak, it may have done so with a lower threshold for defining clusters and more rapid receipt and analyses of HIV genetic sequences.

RV144 vaccine imprinting constrained HIV-1 evolution following breakthrough infection.

The scale of the HIV-1 epidemic underscores the need for a vaccine. The multitude of circulating HIV-1 strains together with HIV-1's high evolvability hints that HIV-1 could adapt to a future vaccine. Here, we wanted to investigate the effect of vaccination on the evolution of the virus post-breakthrough infection. We analyzed 2,635 HIV-1 env sequences sampled up to a year post-diagnosis from 110 vaccine and placebo participants who became infected in the RV144 vaccine efficacy trial. We showed that the Env signature sites that were previously identified to distinguish vaccine and placebo participants were maintained over time. In addition, fewer sites were under diversifying selection in the vaccine group than in the placebo group. These results indicate that HIV-1 would possibly adapt to a vaccine upon its roll-out.

Phylogenetic estimates of SARS-CoV-2 introductions into Washington State.

BACKGROUND: The first confirmed case of SARS-CoV-2 in North America was identified in Washington state on January 21, 2020. We aimed to quantify the number and temporal trends of out-of-state introductions of SARS-CoV-2 into Washington. METHODS: We conducted a phylogenetic analysis of 11,422 publicly available whole genome SARS-CoV-2 sequences from GISAID sampled between December 2019 and September 2020. We used maximum parsimony ancestral state reconstruction methods on time-calibrated phylogenies to enumerate introductions/exports, their likely geographic source (e.g. US, non-US, and between eastern and western Washington), and estimated date of introduction. To incorporate phylogenetic uncertainty into our estimates, we conducted 5,000 replicate analyses by generating 25 random time-stratified samples of non-Washington reference sequences, 20 random polytomy resolutions, and 10 random resolutions of the reconstructed ancestral state. RESULTS: We estimated a minimum 287 separate introductions (median, range 244-320) into Washington and 204 exported lineages (range 188-227) of SARS-CoV-2 out of Washington. Introductions began in mid-January and peaked on March 29, 2020. Lineages with the Spike D614G variant accounted for the majority (88%) of introductions. Overall, 61% (range 55-65%) of introductions into Washington likely originated from a source elsewhere within the US, while the remaining 39% (range 35-45%) likely originated from outside of the US. Intra-state transmission accounted for 65% and 28% of introductions into eastern and western Washington, respectively. CONCLUSIONS: There is phylogenetic evidence that the SARS-CoV-2 epidemic in Washington is continually seeded by a large number of introductions, and that there was significant inter- and intra-state transmission. Due to incomplete sampling our data underestimate the true number of introductions.

Risk compensation after HIV-1 vaccination may accelerate viral adaptation and reduce cost-effectiveness: a modeling study.

Pathogen populations can evolve in response to selective pressure from vaccine-induced immune responses. For HIV, models predict that viral adaptation, either via strain replacement or selection on de novo mutation, may rapidly reduce the effectiveness of an HIV vaccine. We hypothesized that behavioral risk compensation after vaccination may accelerate the transmission of vaccine resistant strains, increasing the rate of viral adaptation and leading to a more rapid decline in vaccine effectiveness. To test our hypothesis, we modeled: (a) the impact of risk compensation on rates of HIV adaptation via strain replacement in response to a partially effective vaccine; and (b) the combined impact of risk compensation and viral adaptation on vaccine-mediated epidemic control. We used an agent-based epidemic model that was calibrated to HIV-1 trends in South Africa, and includes demographics, sexual network structure and behavior, and within-host disease dynamics. Our model predicts that risk compensation can increase the rate of HIV viral adaptation in response to a vaccine. In combination, risk compensation and viral adaptation can, under certain scenarios, reverse initial declines in prevalence due to vaccination, and result in HIV prevalence at 15 years equal to or greater than prevalence without a vaccine.

Test-and-treat coverage and HIV virulence evolution among men who have sex with men.

HIV set point viral load (SPVL), the viral load established shortly after initial infection, is a proxy for HIV virulence: higher SPVLs lead to higher risk of transmission and faster disease progression. Three models of test-and-treat scenarios, mainly in heterosexual populations, found that increasing treatment coverage selected for more virulent viruses. We modeled virulence evolution in a population of men who have sex with men (MSM) with increasing test-and-treat coverage. We extended a stochastic, dynamic network model (EvoNetHIV). We varied relationship patterns (MSM vs. heterosexual), HIV transmission models (increasing vs. plateauing probability of transmission at very high viral loads), and treatment roll-out (with explicit testing or fixed intervals between infection and treatment). In scenarios most similar to previous models (longer relational durations and the plateauing transmission function), we replicated trends previously found: increasing treatment coverage led to increased virulence (0.12 log10 increase in mean population SPVL between 20% and 100% treatment coverage). In scenarios reflecting MSM behavioral data using the increasing transmission function, increasing treatment coverage selected for viruses with lower virulence (0.16 log10 decrease in mean population SPVL between 20% and 100% treatment coverage). These findings emphasize the impact of sexual network conditions and transmission function details on predicted epidemiological and evolutionary outcomes. Varying these features creates very different evolutionary environments, which in turn lead to opposite effects in mean population SPVL evolution. Our results suggest that, under some realistic conditions, effective test-and-treat strategies may not face the previously reported tradeoff in which increasing coverage leads to evolution of greater virulence. This suggests instead that a virtuous cycle of increasing treatment coverage and diminishing virulence is possible.