Alterations in the gut microbiome during HIV infection have been implicated in chronic inflammation, but the role of the oral microbiome in this process is less clear. The article by M. K. Annavajhala, S. D. Khan, S. B. Sullivan, J. Shah, et al. (mSphere 5:e00798-19, 2020, https://doi.org/10.1128/mSphere.00798-19) investigated the relationship between oral and gut microbiome diversity and immune activation in patients with HIV on antiretroviral therapy. In this study, oral microbiome diversity was inversely associated with inflammatory markers such as soluble CD14 (sCD14), but surprisingly similar associations were not seen with gut microbiome diversity. Oral microbiome diversity was also associated with periodontitis in these patients. This study highlights the importance of continuing multisite examinations in studying the gastrointestinal tract microbiome and also stimulates important directions for future research defining the role of the oral-gut axis in HIV-associated inflammation.

Dolutegravir (DTG) is a preferred drug for initial treatment of human immunodeficiency virus type 1 infection. We present next-generation sequencing analysis of integrase genotypes during a period of virologic failure in a treatment-naive man who initiated tenofovir disoproxil fumarate/emtricitabine plus DTG.

Objective: Oral preexposure prophylaxis (PrEP) is highly effective in preventing HIV-1 acquisition, yet it is underutilized among at-risk populations. In this pilot quality improvement (QI) initiative, we sought to identify barriers to PrEP implementation and create interventions to improve access to PrEP in a primary care clinic for homeless veterans. Methods: The setting was a large homeless primary care clinic at the Veterans Affairs in an urban area with high HIV prevalence. A root cause analysis was performed to identify barriers to PrEP expansion in the primary care clinic. Targeted interventions to improve provider knowledge and patient access to PrEP were implemented by the QI team. Results: Root cause analysis revealed 3 primary barriers to PrEP expansion in the primary care clinic: institutional limitations for prescribing PrEP, inconsistent screening and recognition of eligible patients by clinic staff, and lack of clinic workflow processes to support PrEP prescription. A multidisciplinary focus group found low levels of PrEP awareness and knowledge, with only 22% of providers reporting comfort discussing PrEP with patients. This improved to 40% of providers following targeted clinic educational interventions. The QI team also developed a pathway for primary care providers to obtain institutional PrEP prescribing privileges and used work groups to develop clinic workflows and protocols for PrEP. At the end of the intervention, at least 50% of primary care providers in the clinic had initiated PrEP in a new patient. Conclusions: We describe a multidisciplinary QI model to implement PrEP within a primary care setting serving Veterans and persons experiencing homelessness. Our program successfully addressed provider knowledge deficits and improved primary care capacity to prescribe PrEP. The primary care clinic can be a viable and important clinical setting to improve access to PrEP for HIV prevention, especially for vulnerable populations.

Ex vivo mucosal explants have become a mainstay of HIV-1 studies using human tissue. In this study, we examine the baseline phenotypic and virologic differences between biopsies derived from the small intestine (SI) and large intestine (LI) for use in ex vivo explant studies. To do this, we collected endoscopic mucosal biopsies from both SI and LI from the same healthy, HIV-seronegative participants. Mucosal mononuclear cell phenotypes and quantity were compared using flow cytometry. Comparative HIV-1 infectibility of the explants was assessed using an ex vivo explant HIV-1 infection assay. We found that all biopsies had similar numbers of T cells per biopsy. While the percentage of CD4⁺ T cells from SI biopsies expressed significantly more activation markers (CD38, HLA-DR) and HIV coreceptors (CXCR4, CCR5), the absolute numbers of activated CD4⁺ T cells were similar between both sites. LI explants, however, supported more efficient HIV-1 infection, as evidenced by earlier rise in p24 accumulation and greater percent of infected explants at limiting infectious doses. These results suggest that explants from LI biopsies support more efficient HIV-1 infection than SI biopsies, despite similar numbers of available, activated HIV-1 target cells. These findings highlight important differences in LI and SI explants, which must be considered in designing and interpreting ex vivo HIV-1 infection studies, and suggest that factors within the tissue other than target cell number and activation state may play a role in regulating HIV-1 infection.

Dolutegravir (DTG) is a preferred drug for initial treatment of human immunodeficiency virus type 1 infection. We present next-generation sequencing analysis of integrase genotypes during a period of virologic failure in a treatment-naive man who initiated tenofovir disoproxil fumarate/emtricitabine plus DTG.

Objective

Chronic HIV-1 infection leads to widespread inflammation and immune dysregulation. The gastrointestinal mucosa, a primary site for HIV-1 replication, is thought to play a significant role in this response. MicroRNAs (miRs) are small noncoding RNAs that regulate gene expression, including immune activation and inflammation. Here we investigate miR expression and function in the colonic mucosa during HIV-1 infection.

Design and methods

Using miR profiling, we examined miR expression in the colonic mucosa of HIV-infected patients. These miRs were further parsed to identify those that most likely function in HIV-related inflammation. Using bioinformatics tools, we identified potential target genes which were confirmed using in-vitro functional testing.

Results

We identified 12 miRs that were differentially expressed in the colonic mucosa of HIV-infected patients with high versus undetectable plasma viral concentrations. Of these, both miR-26a and miR-29a were downregulated in untreated HIV-1 infection, yet not in the colonic mucosa from inflammatory bowel disease. This downregulation occurs within the first hours after infection. These miRs were further shown to directly target IL-6 and STAT3, respectively, with similar changes confirmed in an ex-vivo explant infection model.

Conclusion

miR-26a and miR-29a levels are decreased in the colonic mucosa during chronic HIV-1 infection, and this change may be initiated during acute infection. Both miRs de-repress the IL-6/STAT3 signaling pathway, which could contribute to increased inflammation during infection. These miRs may represent novel therapeutic targets for HIV-1-associated inflammation in the colonic mucosa.

Background

Methamphetamine (MA) use is associated with sexual risk behavior as well as systemic and mucosal inflammation, suggesting parallel biological and behavioral mechanisms of HIV transmission among men who have sex with men (MSM) who use MA. Data evaluating the combined biological effects of MA use with concomitant rectal gonococcal and/or chlamydial (GC/CT) infection on inflammation are limited.

Setting

Secondary analysis of stored rectal and plasma specimens from 100 MSM participating in an NIDA-funded longitudinal cohort in Los Angeles, CA.

Methods

This cross-sectional analysis evaluated systemic and rectal inflammatory markers under 2 conditions: (1) recent MA use (by urine drug screen) and (2) rectal GC/CT infection. We evaluated 50 participants with recent MA use (25 with and 25 without rectal GC/CT) and 50 MSM without MA use (25 with and 25 without rectal GC/CT). Log-transformed plasma and rectal immune markers were regressed on MA exposure and rectal GC/CT, controlling for HIV status and age.

Results

Median age was 32 (range 19-45) years, and 58% of participants were living with HIV. Plasma tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-8, IL-1ß, and rectal IL-6 were associated with rectal GC/CT and MA use, independent of HIV status. Higher levels of rectal TNF-α, IL-1ß, and IL-17a were associated with rectal GC/CT.

Conclusions

Systemic and rectal inflammation was positively associated with rectal GC/CT and MA use. Condomless sex in the setting of GC/CT- and MA-induced immune activation may provide a basis for synergistic biobehavioral mechanisms that promote HIV/STI transmission among MSM who use MA.

BACKGROUND: Neisseria gonorrheae and Chlamydia trachomatis are associated with mucosal inflammation and human immunodeficiency virus 1 (HIV-1) transmission. We assessed levels of inflammatory cytokines in men who have sex with men (MSM) with and without rectal gonorrhea and/or chlamydia in Lima, Peru. METHODS: We screened 605 MSM reporting condomless receptive anal intercourse for rectal N. gonorrheae/C. trachomatis using nucleic acid testing. We identified 101 cases of gonorrhea and/or chlamydia and randomly selected 50 N. gonorrheae/C. trachomatis positive cases and matched 52 negative controls. We measured levels of IL-1β, IL-6, IL-8, and TNF-α in rectal secretions. Tests for HIV-1, rectal N. gonorrheae/C. trachomatis, and mucosal cytokines were repeated after 3 and 6 months. Cytokine levels in cases and uninfected controls were compared using Wilcoxon rank-sum tests and linear regression. RESULTS: MSM with gonorrhea/chlamydia had elevated levels of all cytokines in rectal mucosa compared with matched controls (all P values <.001). Following antibiotic treatment there were no significant differences in cytokine levels at 3- or 6-month follow-up evaluations (all P values >.05). DISCUSSION: Rectal gonorrhea/chlamydia infection is associated with transient mucosal inflammation and cytokine recruitment. Our data provide proof of concept for rectal sexually transmitted infection screening as an HIV prevention strategy for MSM. Clinical Trials Registration. NCT03010020.

Background

Substance use decreases the likelihood of achieving undetectable HIV viremia; however, the comparative effects by drug have not been fully described. In this study, we compare the effects of methamphetamine use versus other drugs on viremia in sexual minority men on antiretroviral therapy (ART).

Methods

HIV-positive participants currently on ART (N = 230) were selected from an ongoing cohort of diverse young sexual minority men (mSTUDY) enrolled from August 2014 to May 2018. Substance use and sociodemographic factors associated with viremia outcomes were assessed using ordinal regression analysis with generalized estimating equations. Viremia outcomes were grouped as undetectable (<20 copies/mL), low level suppressed (21-200 copies/mL), or not suppressed (>200 copies/mL).

Results

The prevalence of drug use across 825 study visits was 73 %, with methamphetamine use most prevalent (50 %). After adjusting for unstable housing and ART adherence, methamphetamine use, either alone (adjusted OR = 1.87; 95 % CI 1.03-3.40) or with other drugs (adjusted OR = 1.82; 95 % CI 1.12-2.95), was associated with higher odds of increasing viremia compared to no drug use. Other drug use excluding methamphetamine did not show a similar association (adjusted OR = 1.29; 95 % CI 0.80-2.09). Among our study population, nearly half the instances of viremia could be reduced if methamphetamine was discontinued (attributable fraction = 46 %; 95 % CI 3-71 %).

Conclusions

Methamphetamine use, either alone or in combination with other drugs, is associated with failure of viral suppression among sexual minority men on ART independent of adherence and sociodemographic factors. This accounts for nearly half of the observed instances of unsuppressed viremia in this study.

Risk of HIV acquisition varies, and some individuals are highly HIV-1-exposed, yet, persistently seronegative (HESN). The immunologic mechanisms contributing to this phenomenon are an area of intense interest. As immune activation and inflammation facilitate disease progression in HIV-1-infected persons and gastrointestinal-associated lymphoid tissue is a highly susceptible site for transmission, we hypothesized that reduced gut mucosal immune reactivity may contribute to reduced HIV-1 susceptibility in HESN men with a history of numerous rectal sexual exposures. To test this, we used ex vivo mucosal explants from freshly acquired colorectal biopsies from healthy control and HESN subjects who were stimulated with specific innate immune ligands and inactivated whole pathogens. Immune reactivity was then assessed via cytokine arrays and proteomic analysis. Mucosal immune cell compositions were quantified via immunohistochemistry. We found that explants from HESN subjects produced less proinflammatory cytokines compared with controls following innate immune stimulation; while noninflammatory cytokines were similar between groups. Proteomic analysis identified several immune response proteins to be differentially expressed between HIV-1-stimulated HESN and control explants. Immunohistochemical examination of colorectal mucosa showed similar amounts of T cells, macrophages, and dendritic cells between groups. The results of this pilot study suggest that mucosal innate immune reactivity is dampened in HESN versus control groups, despite presence of similar densities of immune cells in the colorectal mucosa. This observed modulation of the rectal mucosal immune response may contribute to lower risk of mucosal HIV-1 transmission in these individuals.