Mentored Scientist Award

Background: Resource limitations currently preclude use of routine plasma HIV RNA testing in much of Africa. Alternative approaches for detecting treatment failure are known to have poor sensitivity and specificity; however, the impact that lack of viral load testing will have on patient mortality remains unclear.

Uganda has one of the highest per capita rates of alcohol consumption in the world coupled with a generalized HIV epidemic that affects 5-7% of the adult population. A growing body of research has shown that alcohol use is strongly correlated with sexual risk behavior, but the strength of this association among HIV+ adults remains unclear. Understanding the mechanisms by which alcohol use is related to unprotected sexual intercourse among HIV+ individuals is essential for developing effective secondary HIV prevention interventions.

Background: Resource limitations currently preclude use of routine plasma HIV RNA testing in much of Africa. Alternative approaches for detecting treatment failure are known to have poor sensitivity and specificity; however, the impact that lack of viral load testing will have on patient mortality remains unclear.

Millions of HIV-infected Africans now receive life-saving antiretroviral therapy (ART). However, mortality remains high, and persistent immune activation during early ART-mediated viral suppression is an independent predictor of mortality in this setting. Studies have shown that generalized immune activation accelerates clinical progression of untreated HIV disease, persists during therapy, predicts poor immune recovery during suppressive ART, and may lead to increased mortality. One potential inflammatory pathway mediating morbidity and mortality is the tryptophan oxidative (TOx) pathway.

Untreated HIV-1 infection is characterized by a progressive depletion of CD4 T cells that clinically culminates in AIDS. Our understanding of the mechanisms underlying CD4 T-cell death remains rudimentary. By infecting lymphoid cell cultures ex vivo, we have found that the vast majority of HIV-1-infected CD4 T cells do not die as a result of productive viral infection, but rather these cells die due to abortive infection where cytosolic viral DNA triggers a suicidal antiviral innate immune response.

Tuberculosis (TB) is the leading cause of death for people infected with HIV worldwide. Active TB disease is largely driven by a vast reservoir of latent TB infection (LTBI), most of which has already been established by the age of five. ^1,2 However, the epidemiology of TB acquisition prior to the age of 5 is poorly understood in high TB burden countries. Additionally, there is a significant gap in knowledge of TB acquisition dynamics in HIV-exposed, un-infected children - a growing group of children due to advances in Prevention of Mother to Child Transmission.

Tuberculosis (TB) is the leading cause of death for people infected with HIV worldwide. Active TB disease is largely driven by a vast reservoir of latent TB infection (LTBI), most of which has already been established by the age of five. ^1,2 However, the epidemiology of TB acquisition prior to the age of 5 is poorly understood in high TB burden countries. Additionally, there is a significant gap in knowledge of TB acquisition dynamics in HIV-exposed, un-infected children - a growing group of children due to advances in Prevention of Mother to Child Transmission.

The use of highly active antiretroviral therapy (HAART) has resulted in the marked decline in the morbidity and mortality associated with HIV infection. However, despite this success, current antiretroviral therapy has limitations and does not achieve a cure. Eradication of HIV will likely require a combination of strategies, including therapies that bolster the host?s immune system and that re-activate the HIV latent reservoirs. The majority of the latent reservoir in treated patients resides in the secondary lymphoid tissues including lymph nodes.

The use of highly active antiretroviral therapy (HAART) has resulted in the marked decline in the morbidity and mortality associated with HIV infection. However, despite this success, current antiretroviral therapy has limitations and does not achieve a cure. Eradication of HIV will likely require a combination of strategies, including therapies that bolster the host?s immune system and that re-activate the HIV latent reservoirs. The majority of the latent reservoir in treated patients resides in the secondary lymphoid tissues including lymph nodes.

In contrast to prior strategies for the prevention of mother-to-child transmission (PMTCT) of HIV that employed antiretroviral monotherapy and short courses of combination prophylaxis, the 2013 World Health Organization Consolidated Guidelines now recommend combination antiretroviral therapy (cART) for all HIV-infected pregnant and breastfeeding women, regardless of CD4 cell count, and encourage lifelong cART (Option B+). B+ has the potential to improve maternal health and mortality and reduce vertical transmission and sexual transmission to partners.