The factors responsible for the initial fall in viremia during acute HIV-1 infection are incompletely understood. The appearance of HIV-1 specific cytotoxic lymphocytes (CTL) has been temporally correlated with the decline in viremia, before the appearance of detectable neutralizing antibodies, suggesting that the cellular immune response may initially contain viral replication. Alternatively, mathematical modeling suggests that the decline in viremia is the result of expected population dynamics of a lymphotropic cytopathic retrovirus, and that the sharp decline in viremia is a result of diminished numbers of infectable activated CD4 cells. Almost all studies of CTL responses during primary infection have been limited to analysis of recognition of laboratory strains of virus, such that the breadth and specificity of the initial response is not known. Although recent longitudinal studies in a single person with primary infection suggest that CTL can exert immune pressure, as evidenced by the emergence of sequence variation within a dominant CTL epitope, the ability of CTL or CD8 cells to actually control replication of the initial virus present has not been demonstrated. I propose to perform a detailed analysis of the antiviral cellular immune response in primary HIV-1 infection. We have developed in vitro assays which allow for the direct examination of antiviral activity of CD8 cells and CTL clones. We are also developing an adapted novel technique for the rapid expression of PCR amplified virus genes using a combination of vaccinia infection-plasmid transfection, such that responses to autologous virus can be assessed efficiently. Using these techniques, I will conduct a detailed study of the antiviral activity of CTL and CD8 cells during the critical period of primary infection when the viral load is declining, in order to determine the contribution of the immune system to this decline. Through a cohort of persons with primary infection in Boston and through an established and functional collaboration with UCSF, we have access to blood and tissue specimens from persons during primary infection, prior to seroconversion and prior to the establishment of the viral set point. An analysis of the antiviral immune response in these individuals will provide important information regarding the correlates of protective immunity and help guide the design of therapeutic strategies and vaccines. Specifically, I propose to: 1. Characterize the magnitude, breadth and specificity of the CTL response to autologous virus in blood and tissues at the time of primary infection, when peak viremia is declining. 2. Determine the ability of CD8 cells and CTL clones to inhibit replication of autologous virus at the time of declining viremia during acute infection.
|Izikson, L; Klein, R S; Charo, I F et al. (2000) Resistance to experimental autoimmune encephalomyelitis in mice lacking the CC chemokine receptor (CCR)2. J Exp Med 192:1075-80|