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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.Why are males more susceptible to severe COVID-19 than females? In this Perspective, Sabra Klein and colleagues consider the sex differences in the immune system that may contribute to this sex bias.

Globally, the majority of people living with HIV are women or girls, but they have been a minority of participants in clinical trials and observational studies of HIV. Despite this underrepresentation, differences in the pathogenesis of HIV have been observed between men and women, with contributions from both gender- and sex-based factors. These include differences in the risk of HIV acquisition, in viral load set point and immune activation in responses to viremia, and differences in HIV reservoir maintenance. These differences obligate adequate study in both males and females in order to optimize treatments, but also provide a powerful leverage point for delineating the mechanisms of HIV pathogenesis. The shifts in exposure to sex steroid hormones across a lifespan introduce additional complexity, which again can be used to focus on either genetic or hormonal influences as the driver of an outcome. In this Review, we discuss consistent and reproducible differences by sex across the spectrum of HIV, from acquisition through pathogenesis, treatment, and cure, and explore potential mechanisms and gaps in knowledge.

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.

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.

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.

Despite evidence of sex-specific pathogenesis, few studies of infectious diseases report or analyse sex or gender, unless it is the primary focus. Using HIV as an example, it is argued here that this leaves potentially informative data unexplored and that integrating sex and gender in analyses may accelerate research in microbial pathogenesis.

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.

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. Summary 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).

Background Systematic tuberculosis (TB) screening is recommended for all people with HIV (PWH) because of its potential to improve TB outcomes through earlier diagnosis and treatment initiation. As such, systematic screening may be particularly important for men, who experience excess TB prevalence and mortality compared to women. We assessed sex differences among PWH undergoing systematic TB screening, including TB prevalence and severity, diagnostic accuracy of screening tools, and TB outcomes. Methods We enrolled and followed adults with HIV (CD4 ≤ 350 cells/µL) initiating antiretroviral therapy (ART) at two HIV/AIDS clinics in Uganda from July 2013 to December 2016. All participants underwent TB screening and sputum collection for TB testing (Xpert MTB/RIF [Xpert], culture). We evaluated diagnostic accuracy of four WHO-recommended TB screening strategies (symptom screen; C-reactive protiein [CRP]; symptom screen followed by CRP, if symptomatic [symptoms + CRP]; Xpert) for culture-positive TB and compared TB prevalence, days-to-treatment initiation, and 3-month mortality by sex. Results Of 1,549 participants, 727 (46.9%) were male and 236 (15.2%) had culture-positive TB. Compared to females, males had lower pre-ART CD4 counts (median 139 vs. 183 cells/µL, p  < 0.001), higher TB prevalence (20.5% vs. 10.6%, p  < 0.001), and higher mycobacterial load as measured by Xpert semi-quantitative grade ( p  = 0.03). Sensitivity was high (≥ 89.8%) for all screening strategies except Xpert (Xpert sensitivity 57.2%) and did not differ by sex. Specificity varied widely from 13.9% for symptom screen to 99.2% for Xpert, and was 5–15% lower for males than females for symptom screen, CRP, and symptoms + CRP. Among PWH with culture-positive TB, median days-to-treatment initiation (2 vs. 4, p  = 0.13) and 3-month mortality (9.4% vs. 9.2%, p  = 0.96) were similar for males and females. Conclusions Although ART-naïve males undergoing systematic screening had more advanced HIV and TB than females, days-to-TB treatment initiation and early TB mortality were similar, suggesting that systematic TB screening has the potential to reduce sex-based disparities in TB outcomes.

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.