Kerri J. Penrose

Clonally expanded CD4+ T cells can produce infectious HIV-1 in vivo

Significance Reservoirs of HIV-infected cells persist during antiretroviral therapy, and understanding persistence is essential to develop HIV curative strategies. During replication, HIV integrates into the host genome; most proviruses are not infectious, but some with replication-competent HIV persist. Cells with integrated HIV can proliferate, potentially expanding the reservoir, but whether cells with replication-competent HIV actually undergo expansion is unknown. HIV reactivation is often lethal to infected cells, and others have reported finding no replication-competent HIV in expanded populations. We describe a highly expanded clone containing infectious HIV that was the source of viremia for years in a patient. Clonally expanded populations can represent a long-lived reservoir of HIV. Curative strategies will require targeting this persistence mechanism. Reservoirs of infectious HIV-1 persist despite years of combination antiretroviral therapy and make curing HIV-1 infections a major challenge. Most of the proviral DNA resides in CD4+T cells. Some of these CD4+T cells are clonally expanded; most of the proviruses are defective. It is not known if any of the clonally expanded cells carry replication-competent proviruses. We report that a highly expanded CD4+ T-cell clone contains an intact provirus. The highly expanded clone produced infectious virus that was detected as persistent plasma viremia during cART in an HIV-1–infected patient who had squamous cell cancer. Cells containing the intact provirus were widely distributed and significantly enriched in cancer metastases. These results show that clonally expanded CD4+T cells can be a reservoir of infectious HIV-1.

Selection of Rilpivirine-Resistant HIV-1 in a Seroconverter From the SSAT 040 Trial Who Received the 300-mg Dose of Long-Acting Rilpivirine (TMC278LA)

The injectable long-acting formulation of rilpivirine (TMC278LA) is a promising preexposure prophylaxis (PrEP) candidate for prevention of human immunodeficiency virus type 1 (HIV-1) infection. We evaluated HIV-1 in plasma obtained from an unexpected seroconverter in the 300-mg arm of the SSAT040 TMC278LA pharmacokinetic study for rilpivirine (RPV) resistance. Infection with wild-type HIV-1 was confirmed on day 84 after TMC278LA injection, and the K101E mutation was detected on day 115. Plasma-derived HIV-1 clones containing K101E had 4-fold increased resistance to RPV and 4-8-fold increased cross-resistance to etravirine, nevirapine, and efavirenz compared with wild type HIV-1 plasma-derived clones from the same individual. This case is a unique instance of infection with wild-type HIV-1 and subsequent selection of resistant virus by persistent exposure to long-acting PrEP.

Y chromosome and HIV DNA detection in vaginal swabs as biomarkers of semen and HIV exposure in women.

Background The inability to quantify sexual exposure to HIV limits the power of HIV prevention trials of vaccines, microbicides, and preexposure prophylaxis in women. We investigated the detection of HIV-1 and Y chromosomal (Yc) DNA in vaginal swabs from 83 participants in the HPTN 035 microbicide trial as biomarkers of HIV exposure and unprotected sexual activity. Methods One hundred forty-three vaginal swabs from 85 women were evaluated for the presence of Yc DNA (Quantifiler Duo DNA quantification kit; Applied Biosystems) and total HIV-1 DNA (single-copy in-house quantitative polymerase chain reaction assay). Y DNA detection was paired with self-reported behavioral data with regard to recent coitus (⩽1 week before collection) and condom usage (100% vs. <100% compliance). Results Yc DNA was detected in 62 (43%) of 143 swabs. For the 126 visits at which both behavioral data and swabs were collected, Yc DNA was significantly more frequent in women reporting less than 100% condom usage (odds ratio, 10.69; 95% confidence interval, 2.27–50.32; P = 0.003). Notably, 27 (33%) of 83 swabs from women reporting 100% condom usage were positive for Yc DNA. HIV DNA was only detected in swabs collected postseroconversion. Conclusions The use of Yc DNA in HIV prevention trials could reliably identify subgroups of women who have unprotected sexual activity and could provide valuable exposure-based estimates of efficacy.

Cost-effectiveness of Injectable Preexposure Prophylaxis for HIV Prevention in South Africa

BACKGROUND Long-acting injectable antiretrovirals such as rilpivirine (RPV) could promote adherence to preexposure prophylaxis (PrEP) for human immunodeficiency virus (HIV) prevention. However, the cost-effectiveness of injectable PrEP is unclear. METHODS We constructed a dynamic model of the heterosexual HIV epidemic in KwaZulu-Natal, South Africa, and analyzed scenarios of RPV PrEP scale-up for combination HIV prevention in comparison with a reference scenario without PrEP. We estimated new HIV infections, life-years and costs, and incremental cost-effectiveness ratios (ICERs), over 10-year and lifetime horizons, assuming a societal perspective. RESULTS Compared with no PrEP, unprioritized scale-up of RVP PrEP covering 2.5%-15% of adults prevented up to 9% of new infections over 10 years. HIV prevention doubled (17%) when the same coverage was prioritized to 20- to 29-year-old women, costing

Deciphering the Effects of Injectable Pre-exposure Prophylaxis for Combination Human Immunodeficiency Virus Prevention

10 880-

Frequent Cross-Resistance to Dapivirine in HIV-1 Subtype C-Infected Individuals on Failing First-Line Antiretroviral Therapy in South Africa

19 213 per infection prevented. Prioritization of PrEP to 80% of individuals at highest behavioral risk achieved comparable prevention (4%-8%) at <1% overall coverage, costing

Influence of a loop electrosurgical excision procedure (LEEP) on levels of cytokines in cervical secretions

298-

Frequent cross-resistance to rilpivirine among subtype C HIV-1 from first-line antiretroviral therapy failures in South Africa:

1242 per infection prevented. Over lifetime, PrEP scale-up among 20- to 29-year-old women was very cost-effective (<

Objective Measurement of Inaccurate Condom Use Reporting Among Women Using Depot Medroxyprogesterone Acetate for Contraception

1600 per life-year gained), dominating unprioritized PrEP, while risk prioritization was cost-saving. PrEPs 10-year impact decreased by almost 50% with increases in ICERs (up to 4.2-fold) in conservative base-case analysis. Sensitivity analysis identified PrEPs costs, efficacy, and reliability of delivery as the principal drivers of uncertainty in PrEPs cost-effectiveness, and PrEP remained cost-effective under the assumption of universal access to second-line antiretroviral therapy. CONCLUSIONS Compared with no PrEP, prioritized scale-up of RPV PrEP in KwaZulu-Natal could be very cost-effective or cost-saving, but suboptimal PrEP would erode benefits and increase costs.

Studies of Immune Function In the Inherited Bone Marrow Failure Syndromes.

Injectable antiretrovirals including non-nucleoside reverse transcriptase inhibitors are being evaluated for pre-exposure prophylaxis for HIV prevention. Mathematical modeling suggests that injectable pre-exposure prophylaxis among KwaZulu-Natals at-risk populations could have substantial preventive impact but may increase drug resistance unless highly effective.