The Pathobiology of Primary HIV-1 Infection
Location(s): United States
The proposed research focuses upon events in the central nervous system (CNS) during the earliest weeks and months after initial acquisition of HIV infection, collectively defined as primary HIV infection (PHI). HIV enters the CNS in the earliest stages of infection, and the CNS is a site of persistent viral infection throughout the chronic stages of disease. The underlying hypothesis of this proposal is that initial viral neuroinvasion is important in the neuropathogenesis of HIV, leading to the foundation of persistent and compartmentalized CNS infection, and initiating the process of brain injury. The investigators will longitudinally study 75 subjects presenting during PHI to study the course of host immune and neurological responses and features of cerebrospinal fluid (CSF) HIV quasispecies beginning during this period. The first aim is to understand the relationship between viral burden, early host inflammation, and tissue injury in the CNS, through measurement of CSF markers of inflammation, immune response, and neuronal injury, cerebral metabolites by high-field (4 Tesla) magnetic resonance spectroscopy, and neuropsychological testing. The second aim is to investigate the establishment of compartmentalized CNS infection through use of the heteroduplex tracking assay to detect HIV quasispecies sequence differences between and within CSF and plasma, and through measurement of viral replicative capacity and coreceptor utilization to define the character of early HIV species in each compartment. The final aim is to describe the effect of antiretroviral therapy initiated during PHI on the course of CNS inflammation and neurological responses. This study establishes a cohort for extended follow-up and a repository of banked longitudinal samples for future studies. Our proposed approach will provide crucial information about the clinical importance of early HIV in the nervous system; if immunoactivation-mediated brain injury or the establishment of compartmentalized CNS infection occurs during PHI, early treatment with immune- modulating or antiretroviral medications may provide previously unrecognized long-term neuroprotection. Similarly, detection of beneficial effects of treatment on the CNS during PHI has the potential to profoundly influence treatment strategies in early HIV. The overall goal of this proposal is to ameliorate or prevent HIV-related CNS damage through improved understanding of the early effects and treatment of HIV in the nervous system. Central nervous system (CNS) impairment remains a major complication of HIV-1 infection, and has the potential to affect at least 20% of the 40 million people worldwide who are living with HIV-1. Clarification of the time course of establishment of CNS infection and neurological injury will contribute to an understanding of the significance of the earliest stages of HIV-1 infection in the neuropathogenesis of AIDS. In addition, revealing the early effects of antiretroviral treatment in the CNS may provide a new rationale for initiating antiretroviral therapy in early HIV-1 infection.