Current HIV Research - Volume 16, Issue 3, 2018

Mammalian cells have evolved several mechanisms to prevent or block lentiviral infection and spread. Among the innate immune mechanisms, the signaling cascade triggered by type I interferon (IFN) plays a pivotal role in limiting the burden of HIV-1. In the presence of IFN, human cells upregulate the expression of a number of genes, referred to as IFN-stimulated genes (ISGs), many of them acting as antiviral restriction factors (RFs). RFs are dominant proteins that target different essential steps of the viral cycle, thereby providing an early line of defense against the virus. The identification and characterization of RFs have provided unique insights into the molecular biology of HIV-1, further revealing the complex host-pathogen interplay that characterizes the infection. The presence of RFs drove viral evolution, forcing the virus to develop specific proteins to counteract their activity. The knowledge of the mechanisms that prevent viral infection and their viral counterparts may offer new insights to improve current antiviral strategies. This review provides an overview of the RFs targeting HIV-1 replication and the mechanisms that regulate their expression as well as their impact on viral replication and the clinical course of the disease.

Background: Immune Activation (IA) has been previously documented in both pregnant (PG) and non-PG HIV-1 infected (HIV+) women as well as in HIV- uninfected PG women; the latter as a result of the fetal allograft. To determine whether the combined effects of HIV and pregnancy result in increased IA and whether IA is associated with Microbial Translocation (MT), we performed a prospective, longitudinal, controlled study during pregnancy and the postpartum (PP) period. Methods: HIV+ PG women had biomarkers of IA and MT tested at 12-20 weeks (T1), and 24-36 weeks (T2) of pregnancy and at 6-8 weeks Postpartum (T3). HIV+, non-PG women were tested at comparable time points. HIV- PG women were tested at T1 only. HIV+ women were not started on antiretroviral therapy (ART) until T1. Biomarkers of IA assessed included: CD4DR+, CD4CD38+, CD4DR+CD38+, CD8DR+, CD8CD38+, and CD8DR+CD38+. Biomarkers of MT included LPS, sCD14, and 16SrDNA. Results: 30 HIV+PG women, 18 HIV+ non-PG and 10 HIV-PG were enrolled. In the HIV+ women, there were no differences in median age, viral load, % or absolute CD4 at entry. Significant differences between T1 and T2 and between T1 and T3 were noted in CD8DR+CD38+ in HIV+PG women after ART. CD4DR+, CD4DR+CD38+, and CD8DR+ decreased post ART in HIV+PG women but a decline in IA was less evident in HIV+ non-PG. LPS decreased post ART by T3 in both HIV+PG and HIV+ non-PG groups; 16SrDNA was elevated at all time points in both groups when compared to control values, and declined post ART in the HIV+PG group. A subgroup of HIV-PG at T1 had IA and MT as evidenced by several IA markers and increased LPS. Conclusion: The degree of IA and MT was similar among HIV+PG and HIV+ non-PG women followed longitudinally. There was no incremental increase due to the combined effects of HIV and pregnancy. Several markers of IA and MT (LPS, 16SrDNA) decreased post ART. IA and MT occurred in a subgroup of HIV-PG women during the 1^st trimester. Further study must be done to confirm whether MT consistently occurs in some healthy women during PG.

Background: Antiretroviral treatment (ART) reduces morbidity and mortality caused by human immunodeficiency virus (HIV) infection; however, the emergence of drug-resistant strains poses an important obstacle to treatment success. Using conventional sequencing methods to determine antiretroviral resistance, mutations present in ≥20% of quasispecies can be identified, but drug-resistant minority variants can lead to virologic failure. Objective: We aimed to assess transmitted drug resistance mutations (TDRMs) within minority variants using ultra-deep pyrosequencing (UDPS). Method: Treatment-naive adult patients were included in this observational study. Surveillance TDRMs were classified as ≥20% or at minority variant level (≥2% – <20%). Genotypic sensitivity score calculated by using all pre-treatment drug resistance mutations (PDRMs) was also evaluated. Results: Thirty-six patients were analyzed. Any TDRM at ≥20% level was detected in 8.3% of the patients (n=3). This prevalence increased to 30.6% (n=11) with the inclusion of minority variants. All non-nucleoside reverse transcriptase inhibitor and protease inhibitor-related TDRMs were within minority variants. The genotypic sensitivity score of rilpivirine-based regimens was considerably diminished when minority variants were included in the PDRM analysis. Conclusion: UDPS was used for the first time to assess TDRM in a Turkish HIV cohort and uncovered several mutations hidden within minority variants. UDPS may be preferred to detect PDRMs for avoiding virologic failure with rilpivirine-based ART regimens.

Objective: The study aimed to correlate the status of hepatitis C (HCV) and hepatitis B virus (HBV) co-infection in patients with human immunodeficiency virus (HIV) infection with clinical and demographic data prior to starting highly active antiretroviral therapy (HAART) and assess the impact of HCV and HBV co-infection on the natural history of HIV infection. Patients and Methods: The study involved a total of 836 treatment-naive patients with available serological status for HBV and HCV at the point of therapy initiation. Patients were stratified into four groups: HIV mono-infection, HIV/HCV, HIV/HBV, and HIV/HCV/HBV co-infection. Demographic, epidemiological, immunological and clinical characteristics were analyzed in order to assess the possible impact of HCV and HBV co-infection on HIV - related immunodeficiency and progression to AIDS. Results: The prevalence of HCV and HBV co-infection in our cohort was 25.7% and 6.3%, respectively. Triple HIV/HCV/HBV infection was recorded in 1.7% of the patients. In comparison with those co-infected with HCV, patients with HIV mono-infection had lower levels of serum liver enzymes activity and higher CD4 cell counts, and were less likely to have CD4 cell counts below100 cells/μL and clinical AIDS, with OR 0.556 and 0.561, respectively. No difference in the development of advanced immunodeficiency and/or AIDS was recorded between patients with HIV monoinfection and those co-infected with HBV, or both HCV/HBV. Conclusion: HIV/HCV co-infection was found to be more prevalent than HIV/HBV co-infection in a Serbian cohort. Co-infection with HCV was related to more profound immunodeficiency prior to therapy initiation, reflecting a possible unfavorable impact of HCV on the natural history of HIV infection.

The incidence of HIV-associated Kaposi’s sarcoma (KS) remains high in Zambia in the antiretroviral therapy era. The most efficacious treatment regimen for KS has yet to be established. In both developed and developing countries, treatment regimens have had limited efficacy. Late presentation in Africa affects therapeutic outcomes. Objective: The aim of this study was to determine therapeutic outcomes of epidemic KS patients on combination antiretroviral therapy (cART) after completion of six cycles of Adriamycin, Bleomycin, and Vincristine (ABV) chemotherapy. Methods: This was a descriptive cross-sectional study. Study participants were drawn from a study database of confirmed incident KS patients seen at the Skin Clinic of the University Teaching Hospitals (UTH) during the period between August, 2015 and September, 2016. Results: Of the 38 successfully recruited study participants, a complete response was documented in 18 (47%) after 6 cycles of ABV whereas 20 (53%) experienced a partial response. KS recurrence was observed in 8 (44%) of the individuals that experienced an initial complete response. At the time of the study, clinical assessment revealed that KS lesions had completely regressed in 21 (55%) of all the patients. Conclusion: ABV chemotherapy appears ineffective in long-term resolution of epidemic KS patients on ART. Recurrence rates are high after chemotherapy in patients that experience initially favorable responses to treatment. There is a need to diagnose KS earlier, and to develop more efficacious treatment options in order to reduce recurrence rates for epidemic KS.

Background: Despite decreasing rates of HIV among many populations, HIV-related health disparities among gay, bisexual and other men who have sex with men persist, with disproportional percentages of new HIV diagnoses among racial and ethnic minority men. Despite increasing awareness of HIV pre-exposure prophylaxis (PrEP), PrEP use remains low. In addition to exploring individual-level factors for this slow uptake, structural drivers of PrEP use must also be identified in order to maximize the effectiveness of biomedical HIV prevention strategies. Method: Using cross-sectional data from an ongoing cohort study of young sexual minority men (N=492), we examine the extent to which structural-level barriers, including access to health care, medication logistics, counseling support, and stigma are related to PrEP use. Results: While almost all participants indicated awareness of PrEP, only 14% had ever used PrEP. PrEP use was associated with lower concerns about health care access, particularly paying for PrEP. Those with greater concerns talking with their provider about their sexual behaviors were less likely to use PrEP. Conclusion: Paying for PrEP and talking to one’s provider about sexual behaviors are concerns for young sexual minority men. In particular, stigma from healthcare providers poses a significant barrier to PrEP use in this population. Providers need not only to increase their own awareness of and advocacy for PrEP as an effective risk-management strategy for HIV prevention, but also must work to create open and non-judgmental spaces in which patients can discuss sexual behaviors without the fear of stigma.

Background: Atlanta has been identified as an HIV “hot spot” for Black women and ranks 5th in the US with new infections. Yet little is known about PrEP eligibility or interest among young Black women in Atlanta. Methods: A convenience sample of 1,261 Black women (ages 14-24 years) were recruited from two settings: community venues and sexual health clinics. They provided self-reported sexual behavior data and specimens for laboratory testing for chlamydia (CT) and gonorrhea (GC) infections. For each woman, the number of key self-reported behavioral HIV risk factors was calculated (0-6 factors for the clinic sample, 0-3 factors for the community sample). A single item assessed PrEP interest in the community sample only. Results: Bacterial STI positivity, an indicator for PrEP eligibility, was 20.5% (17.1% CT, 6.3% GC) and 20.9% (18.8% CT, 5.2% GC) for the clinic and community samples, respectively. Of the 144 STI positive women from the clinic sample, 20.1% reported no behavioral risk indicators and 47.2% reported > 2 behavioral indicators. Of the 117 STI positive women from the community sample, 21.4% reported no behavioral risk indicators. 60.7% of the community sample reported they would be likely or very likely to use PrEP if available. Conclusion: Young Black women in Atlanta, whether sampled from community or sexual health settings, are at substantial risk for HIV infection and meet several PrEP eligibility criteria. Scaling up PrEP among women in Atlanta could have significant implications for HIV in this high burden region.