Pilot Award

CD4+ T cell depletion is a hallmark of HIV infection and the CD4+ T cell count is useful for staging patients as they progress to AIDS. However, a bulk lymphocyte count does not take into account the diversity of recognition specificities these T cells have. Using a novel quantitative assay of T cell receptor (TCR) genetic diversity, called AmpliCot, we have found that untreated HIV infection is associated with an order of magnitude decrease in blood T cell diversity and that these decreases correlate with CD4+ counts.

One reason HIV-1-infected subjects fail to control viremia is due to the high rate of mutation of HIV-1, with consequent escape from the immune response, especially from neutralizing antibodies. Approximately 8% of the human genome is composed of human endogenous retroviruses (HERVs). Most HERVs are fixed in the human genome, defective in replication, and transcriptionally silent in normal cells. Previous studies have shown members of the HERV-K (HK) family are reactivated during HIV-1 infection.

Antimalarial chemoprevention is an emerging modality to prevent deaths and morbidity from malaria in children living in highly endemic areas, but there are concerns that it will delay the natural acquisition of antimalarial immunity. Recent studies in mice and humans have challenged this paradigm, and suggest that selective blockade of blood stage infection with antimalarial drugs may paradoxically enhance the development of sterilizing antimalarial immunity, but this has not been tested in field settings.

Standard diagnostic strategies for tuberculosis (TB) are inadequate, and result in misuse of resources in public health programs; overutilization of hospital isolation facilities; and anxiety for patients. The reason for this waste is that standard diagnostic tests for TB are either inaccurate (smear microscopy) or slow (mycobacterial culture).

HIV treatment can improve health and longevity and prevent transmission to sexual and injection drug contacts of persons with HIV. However, realizing the benefits of treatment requires consistent engagement in clinical care and adherence to anti-retroviral medication. Both HIV infection and aging are associated with neurocognitive decline. There may also be synergistic effects between HIV infection and aging that accelerate declines in cognitive function. Cognitive impairment may limit individuals? ability to engage in care, particularly in populations where co-morbidities are common.

There is a fundamental lack of knowledge in identifying HIV infected individuals at high risk of fracture, and determining the effectiveness of treatment. Osteoporosis is usually diagnosed using DXA that provides an estimate of areal bone mineral density (BMD) computed for skeleton sites prone to fracture such as the femoral neck and the lumbar vertebrae.

There is a fundamental lack of knowledge in identifying HIV infected individuals at high risk of fracture, and determining the effectiveness of treatment. Osteoporosis is usually diagnosed using DXA that provides an estimate of areal bone mineral density (BMD) computed for skeleton sites prone to fracture such as the femoral neck and the lumbar vertebrae.

HIV infection can result in a breakdown in intestinal immunity associated with the translocation of immunostimulatory microbial products from the gut lumen to systemic circulation, which initiates and sustains the persistent inflammation that drives progression to AIDS ¹ . In particular, we and others have shown that HIV infection induces a significant loss of IL-17-producing cells, including TH17 cells, that are critical for maintaining the mucosal barrier ^2,3 .

HIV infection can result in a breakdown in intestinal immunity associated with the translocation of immunostimulatory microbial products from the gut lumen to systemic circulation, which initiates and sustains the persistent inflammation that drives progression to AIDS ¹ . In particular, we and others have shown that HIV infection induces a significant loss of IL-17-producing cells, including TH17 cells, that are critical for maintaining the mucosal barrier ^2,3 .

A point-of-care (POC) test that could be implemented at peripheral levels of the health system in low-income countries has been predicted to reduce tuberculosis (TB)-related mortality by one-third. However, no truly POC test is in the diagnostic pipeline. For maximum impact, a POC test should have high specificity such that a positive test result can be followed by the immediate initiation of treatment. However, a highly sensitive but less specific POC test is a more realistic short-term goal and could be used as an important screening tool in peripheral health care settings ?