CD4+ T lymphocytes play a crucial role in eradicating viral infections by providing help for the maintenance of humoral cytotoxic effector responses. Impairment of T-helper function is a hallmark of HIV-1 infections, and our studies indicate that this occurs early in infection and is accompanied by high levels of CD4+ T cell apoptosis. Despite stabilization of viral load HIV-specific helper responses remain virtually undetectable. However, when patients with acute infection receive highly active antiretroviral therapy (HAART), our preliminary studies demonstrate the restoration of HIV-specific T-helper function, in conjunction with a decline in the levels of apoptosis. We hypothesize that early HAART through rapid control of viral replication preserve pathways of T cell regeneration and the CD4+ T cell receptor (TCR) repertoire, and maintains T-helper function. We propose to investigate these issues, focusing on both T-helper and antigen presenting cell (APC) functions through the following Specific Aims: 1. Ascertain if sustained improvement in T-helper function occurs in conjunction with HAART (and other improved regimens). Investigate the kinetics of induction and maintenance of HIV-specific T-helper function. 2. Determine if T-helper dysfunction in acute HIV-1 infection is associated with disruption of the CD4+ TCR repertoire and deletion of HIV-specific CD4+ clones, and if so, can this be reversed or prevented with early HAART. 3. Evaluate the mechanisms associated with CD4+ T cell apoptosis and the effect of early HAART in abrogating these. Patients with primary HIV-1 infection will be recruited through the UW Primary Infection Clinic.
In Aim 1, we will measure CD4+ T cell lymphoproliferation to recall antigens, including HIV-1, analyze expression of key surface molecules indicative of naive and memory cells, and assess the ability of APCs to generate primary and secondary immune responses.
In Aim 2, we will assess the relative levels of CD4+ TCR Vbeta usage and track HIV-specific CD4+ clones by reverse transcriptase-polymerase chain reaction and the VDJ junction size patterns. Finally, in Aim 3, we will examine the role of TNF-alpha and Fas ligand in induction of CD4+ T cell apoptosis. These studies will improve our understanding of how early infection induces T-helper impairment and if aggressive antiretroviral therapy abrogates this effect. Our findings may be key in optimizing current therapeutic strategies for HIV-1 infection.
