Sex Differences in HIV Infection.

Biological sex has wide-ranging impacts on HIV infection spanning differences in acquisition risk, the pathogenesis of untreated infection, impact of chronic treated disease and prospects for HIV eradication or functional cure. This chapter summarizes the scope of these differences and discusses several features of the immune response thought to contribute to the clinical outcomes.

Impact of Tamoxifen on Vorinostat-Induced Human Immunodeficiency Virus Expression in Women on Antiretroviral Therapy: AIDS Clinical Trials Group A5366, The MOXIE Trial.

BACKGROUND: Biological sex and the estrogen receptor alpha (ESR1) modulate human immunodeficiency virus (HIV) activity. Few women have enrolled in clinical trials of latency reversal agents (LRAs); their effectiveness in women is unknown. We hypothesized that ESR1 antagonism would augment induction of HIV expression by the LRA vorinostat. METHODS: AIDS Clinical Trials Group A5366 enrolled 31 virologically suppressed, postmenopausal women on antiretroviral therapy. Participants were randomized 2:1 to receive tamoxifen (arm A, TAMOX/VOR) or observation (arm B, VOR) for 5 weeks followed by 2 doses of vorinostat. Primary end points were safety and the difference between arms in HIV RNA induction after vorinostat. Secondary analyses included histone 4 acetylation, HIV DNA, and plasma viremia by single copy assay (SCA). RESULTS: No significant adverse events were attributed to study treatments. Tamoxifen did not enhance vorinostat-induced HIV transcription (between-arm ratio, 0.8; 95% confidence interval [CI], .2-2.4). Vorinostat-induced HIV transcription was higher in participants with increases in H4Ac (fold increase, 2.78; 95% CI, 1.34-5.79) vs those 9 who did not (fold increase, 1.04; 95% CI, .25-4.29). HIV DNA and SCA plasma viremia did not substantially change. CONCLUSIONS: Tamoxifen did not augment vorinostat-induced HIV RNA expression in postmenopausal women. The modest latency reversal activity of vorinostat, postmenopausal status, and low level of HIV RNA expression near the limits of quantification limited assessment of the impact of tamoxifen. This study is the first HIV cure trial done exclusively in women and establishes both the feasibility and necessity of investigating novel HIV cure strategies in women living with HIV. CLINICAL TRIALS REGISTRATION: NCT03382834.

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

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

Sex-Based Differences in Human Immunodeficiency Virus Type 1 Reservoir Activity and Residual Immune Activation.

Plasma human immunodeficiency virus type 1 (HIV-1) RNA levels in women are lower early in untreated HIV-1 infection compared with those in men, but women have higher T-cell activation and faster disease progression when adjusted for viral load. It is not known whether these sex differences persist during effective antiretroviral therapy (ART), or whether they would be relevant for the evaluation and implementation of HIV-1 cure strategies. We prospectively enrolled a cohort of reproductive-aged women and matched men on suppressive ART and measured markers of HIV-1 persistence, residual virus activity, and immune activation. The frequency of CD4+ T cells harboring HIV-1 DNA was comparable between the sexes, but there was higher cell-associated HIV-1 RNA, higher plasma HIV-1 (single copy assay), and higher T-cell activation and PD-1 expression in men compared with women. These sex-related differences in immune phenotype and HIV-1 persistence on ART have significant implications for the design and measurement of curative interventions.

Sex Differences in Neurocognitive Function in Adults with HIV: Patterns, Predictors, and Mechanisms.

PURPOSE OF REVIEW: Sex differences in cognitive function are well documented yet few studies had adequate numbers of women and men living with HIV (WLWH; MLWH) to identify sex differences in neurocognitive impairment (NCI) and the factors contributing to NCI. Here, we review evidence that WLWH may be at greater risk for NCI. RECENT FINDINGS: We conducted a systematic review of recent studies of NCI in WLWH versus MLWH. A power analysis showed that few HIV studies have sufficient power to address male/female differences in NCI but studies with adequate power find evidence of greater NCI in WLWH, particularly in the domains of memory, speed of information processing, and motor function. Sex is an important determinant of NCI in HIV, and may relate to male/female differences in cognitive reserve, comorbidities (mental health and substance use disorders), and biological factors (e.g., inflammation, hormonal, genetic).

Sex Differences in HIV Infection.

PURPOSE OF REVIEW: This review will outline the multilevel effects of biological sex on HIV acquisition, pathogenesis, treatment response, and prospects for cure. Potential mechanisms will be discussed along with future research directions. RECENT FINDINGS: HIV acquisition risk is modified by sex hormones and the vaginal microbiome, with the latter acting through both inflammation and local metabolism of pre-exposure prophylaxis drugs. Female sex associates with enhanced risk for non-AIDS morbidities including cardiovascular and cerebrovascular disease, suggesting different inflammatory profiles in men and women. Data from research on HIV cure points to sex differences in viral reservoir dynamics and a direct role for sex hormones in latency maintenance. Biological sex remains an important variable in determining the risk of HIV infection and subsequent viral pathogenesis, and emerging data suggest sex differences relevant to curative interventions. Recruitment of women in HIV clinical research is a pathway to both optimize care for women and to identify novel therapeutics for use in both men and women.

Follicular Dendritic Cells Retain Infectious HIV in Cycling Endosomes.

Despite the success of antiretroviral therapy (ART), it does not cure Human Immunodeficiency Virus (HIV) and discontinuation results in viral rebound. Follicular dendritic cells (FDC) are in direct contact with CD4+ T cells and they retain intact antigen for prolonged periods. We found that human FDC isolated from patients on ART retain infectious HIV within a non-degradative cycling compartment and transmit infectious virus to uninfected CD4 T cells in vitro. Importantly, treatment of the HIV+ FDC with a soluble complement receptor 2 purges the FDC of HIV virions and prevents viral transmission in vitro. Our results provide an explanation for how FDC can retain infectious HIV for extended periods and suggest a therapeutic strategy to achieve cure in HIV-infected humans.

Patient attrition between the emergency department and clinic among individuals presenting for HIV nonoccupational postexposure prophylaxis.

BACKGROUND: Nonoccupational postexposure prophylaxis (nPEP) is recommended after a sexual or parenteral exposure to human immunodeficiency virus (HIV). Patients frequently seek care in an emergency department (ED) after an exposure and are usually referred to an HIV clinic for further management. There have been few data on determinants of attrition after presentation to EDs for nPEP. METHODS: From July 2010 to June 2011, we prospectively recorded all referrals to nPEP programs from 2 large EDs at 2 academic medical centers in Boston, Massachusetts. Data were recorded on patient demographics, nature of potential HIV exposures, referrals to and attendance at HIV clinics, and reported completion of 28 days of antiretroviral therapy (ART). Multivariable logistic regression was used to evaluate risk factors for (1) patient attrition between the ED and HIV clinic follow-up and (2) documented completion of ART. RESULTS: Of 180 individuals who were referred to clinic follow-up for nPEP care from the ED, 98 (54.4%) attended a first nPEP clinic visit and 43 (23.9%) had documented completion of a 28-day course of ART. Multivariable analysis revealed older age (adjusted odds ratio [aOR], 0.96; 95% confidence interval [CI], .93-.99) and self-payment (aOR, 0.32; 95% CI, .11-.97) were significant predictors for failing to attend an initial HIV clinic appointment. Women were less likely than men to complete a 28-day ART regimen (aOR, 0.34; 95% CI, .15-.79). CONCLUSIONS: Commonly used nPEP delivery models may not be effective for all patients who present with nonoccupational exposures to HIV. Interventions are needed to improve rates of follow-up and completion of nPEP to reduce the risk of preventable HIV infections.

Changes in Inflammatory Cytokines After Chronic Hepatitis C Treatment Among People Living With HIV.

We aimed to evaluate the effect of hepatitis C virus cure on serum inflammatory markers among people with HIV. Among 127 people with HIV, serum alanine aminotransferase, soluble tumor necrosis factor receptor 1, and inflammatory index score were significantly lower at the 24-week time point in patients who achieved sustained virologic response as compared with those who did not.

Multiancestry sex-stratified genomic associations with HIV viral load and controller status from the ICGH.

Biological sex and host genetics influence HIV pathogenesis. Females have a higher likelihood of spontaneous viral control and lower set point viral load (spVL). No prior studies have assessed sex-specific genetics of HIV. To address this, we performed a sex-stratified genome-wide association study using data from the ICGH. Although it is the largest collection of genomic data in HIV, this multiethnic sample of 9,705 people is 81.3% male. We sought to identify sex-specific genetic variants and genes associated with HIV spVL and control. We confirmed associations in the HLA and CCR5 regions in males and HLA in females. Gene-based analyses detected associations between HIV spVL and PET100, PCP2, XAB2, and STXBP2 only in males. We detected variants with a significant sex-differential effect on spVL in SDC3 and PUM1 (rs10914268) and PSORS1C2 (rs1265159) and on HIV control in SUB1 (rs687659), AL158151.3, PTPA, and IER5L (rs4387067). Those variants have epigenetic and genetic interactions with relevant genes with both cis and trans effects. In summary, we identified sex-shared associations at the single-variant level, sex-specific associations at the gene-based level, and genetic variants with significant differential effects between the sexes.

Proviral location affects cognate peptide-induced virus production and immune recognition of HIV-1-infected T cell clones.

BACKGROUNDHIV-1-infected CD4+ T cells contribute to latent reservoir persistence by proliferating while avoiding immune recognition. Integration features of intact proviruses in elite controllers (ECs) and people on long-term therapy suggest that proviruses in specific chromosomal locations can evade immune surveillance. However, direct evidence of this mechanism is missing.METHODSIn this case report, we characterized integration sites and full genome sequences of expanded T cell clones in an EC before and after chemoradiation. We identified the cognate peptide of infected clones to investigate cell proliferation and virus production induced by T cell activation, and susceptibility to autologous CD8+ T cells.RESULTSThe proviral landscape was dominated by 2 large clones with replication-competent proviruses integrated into zinc finger (ZNF) genes (ZNF470 and ZNF721) in locations previously associated with deeper latency. A third nearly intact provirus, with a stop codon in Pol, was integrated into an intergenic site. Upon stimulation with cognate Gag peptides, infected clones proliferated extensively and produced virus, but the provirus in ZNF721 was 200-fold less inducible. While autologous CD8+ T cells decreased the proliferation of cells carrying the intergenic provirus, they had no effect on cells with the provirus in the ZNF721 gene.CONCLUSIONSWe provide direct evidence that upon activation of infected clones by cognate antigen, the lower inducibility of intact proviruses in ZNF genes can result in immune evasion and persistence.FUNDINGOffice of the NIH Director and National Institute of Dental & Craniofacial Research; NIAID, NIH; Johns Hopkins University Center for AIDS Research.

Hidden in plain sight: sex and gender in global pandemics.

PURPOSE OF REVIEW: The global pandemic caused by the severe acute respiratory virus coronavirus 2 (SARS-CoV-2) has a male bias in mortality likely driven by both gender and sex-based differences between male and female individuals. This is consistent with sex and gender-based features of HIV infection and overlap between the two diseases will highlight potential mechanistic pathways of disease and guide research questions and policy interventions. In this review, the emerging findings from SARS-CoV-2 infection will be placed in the context of sex and gender research in the more mature HIV epidemic. RECENT FINDINGS: This review will focus on the new field of literature on prevention, immunopathogenesis and treatment of SARS-CoV-2 referencing relevant articles in HIV for context from a broader time period, consistent with the evolving understanding of sex and gender in HIV infection. Sex-specific features of epidemiology and immunopathogenesis reported in COVID-19 disease will be discussed and potential sex and gender-specific factors of relevance to prevention and treatment will be emphasized. SUMMARY: Multilayered impacts of sex and gender on HIV infection have illuminated pathways of disease and identified important goals for public health interventions. SARS-CoV-2 has strong evidence for a male bias in disease severity and exploring that difference will yield important insights.

Unlocking the complexity of HIV and Mycobacterium tuberculosis coinfection.

HIV and Mycobacterium tuberculosis (M. tuberculosis) coinfection increases the risk of active tuberculosis (aTB), but how HIV infection and medications contribute to drive risk remains unknown. In this issue of the JCI, Correa-Macedo and Fava et al. investigated alveolar macrophages (AMs) from people living with HIV (PLWH). To mimic the earliest event in tuberculosis (TB), the authors isolated AMs from broncheoalveolar lavage (BAL) of PLWH, healthy individuals, and healthy individuals taking antitretroviral therapy (ART) as preexposure prophylaxis (PrEP) to prevent HIV acquisition. These AMs were exposed to M. tuberculosis and epigenetic configuration, transcriptional responses, and cytokine production were assessed. M. tuberculosis-stimulated AMs from PLWH and from healthy individuals on PrEP showed blunted responses compared with healthy controls. While HIV infection is the major risk factor for TB, these findings suggest that ART may modulate AM responses and potentially contribute to residual risk of aTB in fully treated HIV.

Sex and gender differences in COVID testing, hospital admission, presentation, and drivers of severe outcomes in the DC/Maryland region.

BACKGROUND: Rates of severe illness and mortality from SARS-CoV-2 are greater for males, but the mechanisms for this difference are unclear. Understanding the differences in outcomes between males and females across the age spectrum will guide both public health and biomedical interventions. METHODS: Retrospective cohort analysis of SARS-CoV-2 testing and admission data in a health system. Patient-level data were assessed with descriptive statistics and logistic regression modeling was used to identify features associated with increased male risk of severe outcomes. RESULTS: In 213,175 SARS-CoV-2 tests, despite similar positivity rates (8.2%F vs 8.9%M), males were more frequently hospitalized (28%F vs 33%M). Of 2,626 hospitalized individuals, females had less severe presenting respiratory parameters and males had more fever. Comorbidity burden was similar, but with differences in specific conditions. Medications relevant for SARS-CoV-2 were used at similar frequency except tocilizumab (M>F). Males had higher inflammatory lab values. In a logistic regression model, male sex was associated with a higher risk of severe outcomes at 24 hours (odds ratio (OR) 3.01, 95%CI 1.75, 5.18) and at peak status (OR 2.58, 95%CI 1.78,3.74) among 18-49 year-olds. Block-wise addition of potential explanatory variables demonstrated that only the inflammatory labs substantially modified the OR associated with male sex across all ages. CONCLUSION: Higher levels of clinical inflammatory labs are the only features that are associated with the heightened risk of severe outcomes and death for males in COVID-19. TRIAL REGISTRATION: NA. FUNDING: Hopkins inHealth; COVID-19 Administrative Supplement (HHS Region 3 Treatment Center), Office of the ASPR; NIH/NCI U54CA260492 (SK), NIH/NIA U54AG062333 (SK).

Sex and Gender Differences in Testing, Hospital Admission, Clinical Presentation, and Drivers of Severe Outcomes From COVID-19.

BACKGROUND: Males experience increased severity of illness and mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compared with females, but the mechanisms of male susceptibility are unclear. METHODS: We performed a retrospective cohort analysis of SARS-CoV-2 testing and admission data at 5 hospitals in the Maryland/Washington DC area. Using age-stratified logistic regression models, we quantified the impact of male sex on the risk of the composite outcome of severe disease or death (World Health Organization score 5-8) and tested the impact of demographics, comorbidities, health behaviors, and laboratory inflammatory markers on the sex effect. RESULTS: Among 213 175 SARS-CoV-2 tests, despite similar positivity rates, males in age strata between 18 and 74 years were more frequently hospitalized. For the 2626 hospitalized individuals, clinical inflammatory markers (interleukin-6, C-reactive protein, ferritin, absolute lymphocyte count, and neutrophil:lymphocyte ratio) were more favorable for females than males (P < .001). Among 18-49-year-olds, male sex carried a higher risk of severe outcomes, both early (odds ratio [OR], 3.01; 95% CI, 1.75 to 5.18) and at peak illness during hospitalization (OR, 2.58; 95% CI, 1.78 to 3.74). Despite multiple differences in demographics, presentation features, comorbidities, and health behaviors, these variables did not change the association of male sex with severe disease. Only clinical inflammatory marker values modified the sex effect, reducing the OR for severe outcomes in males aged 18-49 years to 1.81 (95% CI, 1.00 to 3.26) early and 1.39 (95% CI, 0.93 to 2.08) at peak illness. CONCLUSIONS: Higher inflammatory laboratory test values were associated with increased risk of severe coronavirus disease 2019 for males. A sex-specific inflammatory response to SARS-CoV-2 infection may underlie the sex differences in outcomes.

Considering how biological sex impacts immune responses and COVID-19 outcomes.

A male bias in mortality has emerged in the COVID-19 pandemic, which is consistent with the pathogenesis of other viral infections. Biological sex differences may manifest themselves in susceptibility to infection, early pathogenesis, innate viral control, adaptive immune responses or the balance of inflammation and tissue repair in the resolution of infection. We discuss available sex-disaggregated epidemiological data from the COVID-19 pandemic, introduce sex-differential features of immunity and highlight potential sex differences underlying COVID-19 severity. We propose that sex differences in immunopathogenesis will inform mechanisms of COVID-19, identify points for therapeutic intervention and improve vaccine design and increase vaccine efficacy.

HIV Antibody Fc N-Linked Glycosylation Is Associated with Viral Rebound.

Changes in antibody glycosylation are linked to inflammation across several diseases. Alterations in bulk antibody galactosylation can predict rheumatic flares, act as a sensor for immune activation, predict gastric cancer relapse, track with biological age, shift with vaccination, change with HIV reservoir size on therapy, and decrease in HIV and HCV infections. However, whether changes in antibody Fc biology also track with reservoir rebound time remains unclear. The identification of a biomarker that could forecast viral rebound time could significantly accelerate the downselection and iterative improvement of promising HIV viral eradication strategies. Using a comprehensive antibody Fc-profiling approach, the level of HIV-specific antibody Fc N-galactosylation is significantly associated with time to rebound after treatment discontinuation across three independent cohorts. Thus virus-specific antibody glycosylation may represent a promising, simply measured marker to track reservoir reactivation.