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Understanding the impact of concussion history on mental health—mood disorders and substance use—is an essential step in characterizing the psychological and behavioral consequences of concussion and in developing effective treatments. The objective of this study was to examine the association between the history of concussion and substance abuse by investigating both its direct and indirect association via mood disorder. A secondary objective was to determine whether gender moderates the association. A comprehensive survey was administered to 4849 college-age adults that assessed history of concussion; depression, anxiety, and panic disorders using the Patient Health Questionnaire (PHQ); and substance use using the Alcohol Use Disorders Identification Test (AUDIT) (alcohol) and Cannabis Use Disorders Identification Test-Revised (CUDIT) (cannabis). Regression models were used to examine the association between concussion history and substance use. Mood disorders were entered into the model as mediators and gender as a moderator variable. Those with a history of concussion had higher panic, AUDIT, and CUDIT scores than those with no history of concussion, and AUDIT and CUDIT scores showed an interaction between concussion history and gender. The regression models revealed significant direct and indirect (via depression and panic disorder) effects of concussion history on alcohol and cannabis use, which was moderated by gender. Concussion can have long-term psychological consequences and appears to affect both mood and substance use. The results presented demonstrate that the relationship between concussion and substance use is complex with mood disorder mediating the effect.

Defective gastrointestinal barrier function and, in turn, microbial translocation have been identified as significant contributors to persistent inflammation in antiretroviral (ARV)-treated people living with HIV. Metabolic supplementation of short-chain fatty acids (SCFAs), generally produced by the commensal microbiome, may improve these outcomes. Butyrate is a SCFA that is essential for the development and maintenance of intestinal immunity and has a known role in supporting epithelial integrity. Herein we assessed whether supplementation with the dietary supplement sodium butyrate would improve immune reconstitution and reduce inflammation in ARV-treated, simian immunodeficiency virus (SIV)-infected rhesus macaques. We demonstrate that butyrate supplementation does not significantly improve immune reconstitution, with no differences observed in systemic CD4+ T-cell frequencies, T-cell functionality or immune activation, microbial translocation, or transcriptional regulation. Our findings demonstrate that oral administration of sodium butyrate is insufficient to reduce persistent inflammation and microbial translocation in ARV-treated, SIV-infected macaques, suggesting that this therapeutic may not reduce co-morbidities and co-mortalities in treated people living with HIV.

The ability to efficiently establish a new infection is a critical property for human immunodeficiency virus type 1 (HIV-1). Although the envelope protein of the virus plays an essential role in receptor binding and internalization of the infecting virus, the structural proteins, the polymerase and the assembly of new virions may also play a role in establishing and spreading viral infection in a new host. We examined Ugandan viruses from newly infected patients and focused on the contribution of the Gag-Pol genes to replication capacity. A panel of Gag-Pol sequences generated using single genome amplification from incident HIV-1 infections were cloned into a common HIV-1 NL4.3 pol/env backbone and the influence of Gag-Pol changes on replication capacity was monitored. Using a novel protein domain approach, we then documented diversity in the functional protein domains across the Gag-Pol region and identified differences in the Gag-p6 domain that were frequently associated with higher in vitro replication.

The influence of biological sex on disease progression in HIV-1-infected individuals has been focused on the chronic stage of infection, but little is known about how sex differences influence acute HIV-1 infection. We observed profound differences in viral load and CD4(+) T cell activation from the earliest time points in men and women in a Zambian heterosexual acute infection cohort. Women exhibited a >2-fold higher rate of CD4(+) T cell loss despite significantly lower viral loads (VL) than men. The importance of studying acute infection was highlighted by the observation that very early in infection, women exhibited significantly higher levels of CD4(+) T cell activation, a difference that was lost over the first 3 years of infection as activation in men increased. In women, activation of CD4(+) T cells in the acute phase was significantly correlated with plasma levels of 17β-estradiol (E2). However, unlike in men, higher CD4(+) T cell activation in women was not associated with higher VL. In contrast, a higher E2 level in early infection was associated with lower early and set-point VL in women. We attribute this to an inhibitory effect of estradiol on virus replication, which we were able to observe with relevant transmitted/founder viruses in vitro. Thus, estradiol plays a key role in defining major differences between men and women during early HIV-1 infection by contributing to both viral control and CD4(+) T cell loss, an effect that extends into the chronic phase of the disease. IMPORTANCE Previous studies have identified sex-specific differences during chronic HIV-1 infection, but little is known about sex differences in the acute phase, or how disparities in the initial response to the virus may affect disease. We demonstrate that restriction of viral load in women begins during acute infection and is maintained into chronic infection. Despite this, women exhibit more rapid CD4(+) T cell loss than men. These profound differences are influenced by 17β-estradiol, which contributes both to T cell activation and to reduced viral replication. Thus, we conclude that estradiol plays a key role in shaping responses to early HIV-1 infection that influence the chronic phase of disease.

The HIV-1 reservoir consists of latently infected cells that persist despite antiretroviral therapy (ART). Elucidating the proviral genetic composition of the reservoir, particularly in the context of pre-therapy viral diversity, is therefore important to understanding reservoir formation and the persistence of latently infected cells. Here we investigate reservoir proviral variants from 13 Zambian acutely-infected individuals with additional pre-therapy sampling for a unique comparison to the ART-naïve quasispecies. We identified complete transmitted/founder (TF) viruses from seroconversion plasma samples, and additionally amplified and sequenced HIV-1 from plasma obtained one year post-infection and just prior to ART initiation. While the majority of proviral variants in the reservoir were most closely related to viral variants from the latest pre-therapy time point, we also identified reservoir proviral variants dating to or near the time of infection, and to intermediate time points between infection and treatment initiation. Reservoir proviral variants differing by five or fewer nucleotide changes from the TF virus persisted during treatment in five individuals, including proviral variants that exactly matched the TF in two individuals, one of whom had remained ART-naïve for more than six years. Proviral variants during treatment were significantly less divergent from the TF virus than plasma variants present at the last ART-naïve time point. These findings indicate that reservoir proviral variants are archived throughout infection, recapitulating much of the viral diversity that arises throughout untreated HIV-1 infection, and strategies to target and reduce the reservoir must therefore permit for the clearance of proviruses encompassing this extensive diversity., Author summary Despite reducing viremia to levels below the limit of detection in standard assays, effective antiretroviral therapy (ART) does not eradicate cells latently infected with HIV-1. These cells serve as a reservoir for viral rebound if therapy is interrupted; thus, understanding the composition of the reservoir may yield further targets for HIV-1 cure strategies. We have taken a genetic approach to elucidating the reservoir in 13 Zambian subtype C seroconvertors who were followed longitudinally through ART initiation and virologic suppression. In five of the 13 individuals, provirus sequences identical to or differing by five or fewer nucleotides from the transmitted/founder virus were detected, indicating archiving and persistence of early infection variants for more than six years following infection. While the majority of proviral variants in latently infected cells were most closely related to plasma virus circulating immediately prior to treatment initiation, additional variants dating to intermediate time points in the infection were also observed. These findings demonstrate that virus is archived during all stages of ART-naïve infection, and these variants persist throughout ART. HIV-1 cure strategies to eliminate the reservoir must address the broad genetic diversity of a within-host proviral quasispecies including variants archived from acute through chronic infection.

HIV-1 infection is characterized by varying degrees of chronic immune activation and disruption of T-cell homeostasis, which impact the rate of disease progression. A deeper understanding of the factors that influence HIV-1–induced immunopathology and subsequent CD4+ T-cell decline is critical to strategies aimed at controlling or eliminating the virus. In an analysis of 127 acutely infected Zambians, we demonstrate a dramatic and early impact of viral replicative capacity (vRC) on HIV-1 immunopathogenesis that is independent of viral load (VL). Individuals infected with high-RC viruses exhibit a distinct inflammatory cytokine profile as well as significantly elevated T-cell activation, proliferation, and CD8+ T-cell exhaustion, during the earliest months of infection. Moreover, the vRC of the transmitted virus is positively correlated with the magnitude of viral burden in naive and central memory CD4+ T-cell populations, raising the possibility that transmitted viral phenotypes may influence the size of the initial latent viral reservoir. Taken together, these findings support an unprecedented role for the replicative fitness of the founder virus, independent of host protective genes and VL, in influencing multiple facets of HIV-1–related immunopathology, and that a greater focus on this parameter could provide novel approaches to clinical interventions.