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Open Access Publications from the University of California

Recent Work

Since its founding in 1983 by California State Legislature, the California HIV/AIDS Research Program (CHRP) has supported excellent, timely, and innovative research that is attentive to the needs of California, accelerating progress towards prevention, care and treatment for HIV/AIDS. During this time over $250M has been awarded for over 2,000 research projects.

CHRP provides start-up funds for the development of cutting edge research in California, providing critical leverage to bring in federal and private dollars to the state. A 2006 survey of California investigators found that more than five dollars in federal and other grant support was generated for every dollar invested by CHRP in California-based research.

SMAC Mimetics Induce Autophagy-Dependent Apoptosis of HIV-1-Infected Resting Memory CD4+ T Cells.

(2018)

Long-lived resting memory CD4+ T cells (TCM) are a major reservoir of latent HIV infection. We hypothesized that latent HIV-TCM cells are maintained by aberrant expression of cell survival factors, including XIAP, BIRC2/cIAP1, and beclin-1. DIABLO/SMAC mimetics are therapeutic agents that compromise cell survival by hijacking host apoptotic machinery. We found that DIABLO/SMAC mimetics (birinapant, GDC-0152, and embelin) selectively kill HIV-TCM without increasing virus production or targeting uninfected TCM. Treatment of HIV-TCM with DIABLO/SMAC mimetics promoted XIAP and BIRC2 degradation, which triggered autophagy and the formation of a cell death complex consisting of pro-apoptotic (FADD, RIPK1, RIPK3, and caspase 8) and autophagy (ATG5, ATG7, and SQSTM1) proteins. Genetic or pharmacological inhibition of autophagy induction, but not autophagy-mediated degradation, abrogated this interaction and subsequent cell death. Our findings identify a mechanism whereby DIABLO/SMAC mimetics exploit autophagy and apoptotic machinery to selectively induce killing of HIV-TCM without viral reactivation while sparing uninfected cells.

Exploring the preferences of a culturally congruent, peer-based HIV prevention intervention for black men who have sex with men.

(2018)

Background: HIV testing, treatment initiation and treatment adherence have been emphasised for Black men who have sex with men (BMSM). However, many BMSM do not get tested, obtain HIV treatment or adhere to treatment. It is essential to highlight barriers to HIV testing, treatment adherence and the ideal components for an intervention: peer mentors, socioeconomic resources and participant incentives. Methods: Five focus groups (n = 24) were conducted among HIV-negative and HIV-positive BMSM aged ≥18 years in Los Angeles, California, USA to explore motivations and barriers to testing and treatment and the components of an ideal, culturally competent HIV testing intervention for BMSM. Results: Barriers to HIV testing included fear and stigma associated with discovering a HIV-positive status and drug use. Motivations for testing included experiencing symptoms, beginning new relationships, perceptions of risk and peer mentors. Conclusions: Future HIV prevention and treatment efforts should consider these components to improve health outcomes among BMSM.

The Impact Of Medicaid Expansion On People Living With HIV And Seeking Behavioral Health Services.

(2018)

While Medicaid eligibility expansion created health care access for millions in California, its impact on people living with HIV has been more nuanced. Newly covered people living with HIV who have behavioral health care needs now must navigate separate mental health and substance use care systems, instead of receiving them in integrated care settings as they had under the Ryan White HIV/AIDS Program. We conducted forty-seven interviews in the period April 2015-June 2016 to examine the impact of Medicaid expansion on people living with HIV in California who had behavioral health care needs. California's historical division in its Medicaid funding streams created challenges in determining which payer should cover clients' behavioral health care. Compounding these challenges were a perceived lack of cultural competence for serving this population, insufficient infrastructure to facilitate continuity of care, and unmet need for nonmedical supportive services. The multipayer model under health reform has compromised the administrative simplicity and integrated delivery of HIV and behavioral health services previously available to uninsured patients through the Ryan White HIV/AIDS Program.

Cover page of Using a Social Network Strategy to Distribute HIV Self-Test Kits to African American and Latino MSM

Using a Social Network Strategy to Distribute HIV Self-Test Kits to African American and Latino MSM

(2018)

Men who have sex with men (MSM) continue to be disproportionately impacted globally by the HIV epidemic. Studies suggest that HIV self-testing (HIVST) is highly acceptable among MSM. Social network strategies to increase testing are effective in reaching MSM, particularly MSM of color, who may not otherwise test. We tested a social network-based strategy to distribute HIVST kits to African American MSM (AAMSM) and Latino MSM (LMSM).This study was conducted in Alameda County, California, a large, urban/suburban county with an HIV epidemic mirroring the national HIV epidemic.From January 2016 to March 2017, 30 AAMSM, LMSM, and transgender women were trained as peer recruiters and asked to distribute 5 self-test kits to MSM social network members and support those who test positive in linking to care. Testers completed an online survey after their test. We compared peer-distributed HIVST testing outcomes to outcomes from Alameda County's targeted, community-based HIV testing programs using χ tests.Peer-distributed HIVST to 143 social and sexual network members, of whom 110 completed the online survey. Compared with MSM who used the County's sponsored testing programs, individuals reached through the peer-based self-testing strategy were significantly more likely to have never tested for HIV (3.51% vs. 0.41%, P < 0.01) and to report a positive test result (6.14% vs. 1.49%, P < 0.01).Findings suggest that a network-based strategy for self-test distribution is a promising intervention to increase testing uptake and reduce undiagnosed infections among AAMSM and LMSM.

Strategies to Increase HIV Testing Among MSM: A Synthesis of the Literature

(2018)

© 2018, Springer Science+Business Media, LLC, part of Springer Nature. More than 30 years into the HIV epidemic, men who have sex with men (MSM) continue to be disproportionately impacted. It is estimated that worldwide nearly half of MSM infected with HIV are unaware of their status, making HIV testing along with early linkage to care crucial to HIV prevention efforts. However, there remain significant barriers to HIV testing among MSM, due largely to complex issues of layered stigma that deter MSM from accessing traditional, clinic-based testing. We conducted a review and synthesis of the literature on strategies to increase uptake of HIV testing among MSM. We found that social network-based strategies, community-based testing, HIV self-testing, and modifications to the traditional clinic-based model can effectively reach a subset of MSM, but success was often context-specific and there are significant gaps in evidence. We provide recommendations for increasing HIV testing rates and status awareness among MSM.

Effect of rectal douching/enema on rectal gonorrhoea and chlamydia among a cohort of men who have sex with men on HIV pre-exposure prophylaxis

(2018)

© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted. Objectives: Rectal douching/enema (RD) is a common practice among men who have sex with men (MSM) in preparation for sex. RD can break down the rectal mucosal barrier and potentially affect the rectal microbiome. The objective of this study was to understand if RD is associated with acquiring rectal infections (RI) with rectal gonorrhoea (NG) and/or chlamydia (CT). Methods: From 2013 to 2015, 395 adult HIV-uninfected MSM were enrolled in a randomised controlled study for pre-exposure prophylaxis (PrEP) adherence with routine sexual risk survey and testing. Using data from this cohort, baseline differences by RI were assessed using Pearson's and Wilcoxon-Mann-Whitney test. Association between RD and RI was modelled using multivariable logistic regression adjusted for potential confounders (sexual behaviour, substance use and age) selected a priori. Effect modification by number of male partners and sensitivity analysis to rule out reverse causality were also conducted. Results: Of 395 participants, 261 (66%) performed RD and 133 (33%) had at least one NG/CT RI over 48 weeks. Number of condomless anal receptive sex (med: 4, p<0.001), male partners (med:6, p<0.001) and substance use (any of methamphetamine/hallucinogens/dissociative/poppers) (p<0.001) were associated with increased odds of RI. Controlling for potential confounders, odds of prevalent RI were 3.59 (p<0.001, 95% CI 1.90 to 6.78) and incident RI 3.87 (p=0.001, 95% CI 1.78 to 8.39) when douching weekly or more compared with not douching. MSM with more than six male partners had 5.34 (p=0.002, 95% CI 1.87 to 15.31) increased odds of RI when douching weekly or more compared with not douching. Conclusion: Rectal hygiene with RD is a common practice (66%) among HIV-uninfected MSM on PrEP in this study, which increases the odds of acquiring rectal NG and/or CT independent of sexual risk behaviour, substance use and other factors. This suggests interventional approaches targeting rectal hygiene products and practices could reduce sexually transmitted infections.

Results from the post-exposure prophylaxis pilot program (P-QUAD) demonstration project in Los Angeles County

(2018)

Post-exposure prophylaxis (PEP) is a promising but under-utilized strategy for HIV prevention in high-risk populations. Between March 2010 and June 2011, two community-based clinics in Los Angeles County provided PEP in a pilot program to 267 unique individuals. Courses were primarily dispensed to men who have sex with men (84%) and consisted overwhelmingly of a three-drug antiretroviral therapy regimen containing two nucleoside reverse transcriptase inhibitors and either an integrase inhibitor (raltegravir) or a boosted protease inhibitor (lopinavir/ritonavir). Approximately 64% of all PEP courses were followed for at least 12 weeks, and seven individuals seroconverted. Of the seven seroconversions, six had subsequent re-exposure. The low rate of PEP failure calls for expanded funding for PEP in other jurisdictions.

Cover page of Induction of autophagy by PI3K/MTOR and PI3K/MTOR/BRD4 inhibitors suppresses HIV-1 replication

Induction of autophagy by PI3K/MTOR and PI3K/MTOR/BRD4 inhibitors suppresses HIV-1 replication

(2018)

© 2018 Campbell et al. In this study, we investigated the effects of the dual phosphatidylinositol 3-kinase/mechanistic target of rapamycin (PI3K/ MTOR) inhibitor dactolisib (NVP-BEZ235), the PI3K/MTOR/ bromodomain-containing protein 4 (BRD4) inhibitor SF2523, and the bromodomain and extra terminal domain inhibitor JQ1 on the productive infection of primary macrophages with human immunodeficiency type-1 (HIV). These inhibitors did not alter the initial susceptibility of macrophages to HIV infection. However, dactolisib, JQ1, and SF2523 all decreased HIV replication in macrophages in a dose-dependent manner via degradation of intracellular HIV through autophagy. Macrophages treated with dactolisib, JQ1, or SF2523 displayed an increase in LC3B lipidation combined with SQSTM1 degradation without inducing increased cell death. LC3B-II levels were further increased in the presence of pepstatin A suggesting that these inhibitors induce autophagic flux. RNA interference for ATG5 and ATG7 and pharmacological inhibitors of autophagosome-lysosome fusion and of lysosomal hydrolases all blocked the inhibition of HIV. Thus, we demonstrate that the mechanism of PI3K/MTOR and PI3K/MTOR/BRD4 inhibitor suppression of HIV requires the formation of autophagosomes, as well as their subsequent maturation into autolysosomes. These data provide further evidence in support of a role for autophagy in the control of HIV infection and open new avenues for the use of this class of drugs in HIV therapy.

Cover page of Transgender Women Living with HIV Frequently Take Antiretroviral Therapy and/or Feminizing Hormone Therapy Differently Than Prescribed Due to Drug-Drug Interaction Concerns

Transgender Women Living with HIV Frequently Take Antiretroviral Therapy and/or Feminizing Hormone Therapy Differently Than Prescribed Due to Drug-Drug Interaction Concerns

(2017)

© Copyright 2017, Mary Ann Liebert, Inc. 2017. Purpose: Both hormone therapy (HT) and antiretroviral therapy (ART) can be lifesaving for transgender women (TW) living with HIV, but each has side effects and potential drug-drug interactions (DDI). We assessed how concerns about HT-ART interactions affect treatment adherence. Methods: This study used a cross-sectional survey of TW (n = 87) in Los Angeles, CA. Results: Fifty-four percent were living with HIV; 64% used HT. Only 49% of TW living with HIV discussed ART-HT DDI with their provider; 40% reported not taking ART (12%), HT (12%), or both (16%) as directed due to DDI concerns. Conclusion: Imperfect HT/ART use and limited provider communication suggests a need for improved HT-ART integration.