Abstract

Follicular dendritic cells (FDCs) reside in the lymphoid follicles of the secondary lymphoid tissues (sLTs). Following the infection of an individual with human immunodeficiency virus type 1 (HIV-1), viral particles are trapped in massive quantities on the surfaces of FDCs. HIV-1 viral compartments are cell types or tissues between which there is a restriction of virus flow. Compartmentalization of HIV-1 creates numerous sites within the body in which the virus can undergo independent evolution, giving rise to a more diverse total viral population. Given the sessile nature of the FDC, I hypothesized that contrary to common assumptions, FDC-trapped HIV-1 is compartmentalized between different sLTs. Furthermore, given that FDC-trapped HIV-1 represents the major source of virus in the host, I postulated that this compartmentalization would likely impact the diversity of HIV-1 associated with the sLTs. I isolated FDCs, macrophages, and T cells from various sLTs, and sequenced cloned HIV-1 associated with these three cell populations. I subjected the resulting DNA and cDNA sequence data to phylogenetic and other statistical analyses. In support of my hypothesis, I demonstrate that both HIV-1 gp120 and pol sequences cloned from FDCs are compartmentalized between different sLTs. This compartmentalization is even apparent between lymph nodes taken from the same lymph node chain. One of the apparent effects of this compartmentalization is to significantly increase the viral genetic diversity in multiple sLTs when compared with diversity in a single sLT. It also appears that the selective pressures on HIV-1 differ among the sLTs. In addition, when proviruses isolated from macrophages from different sLTs were compared, it was also evident that there is compartmentalization of HIV-1 associated with this cell type as well. Finally, I demonstrate that HIV-1 isolated from an unfractionated population of cells from a single sLT, may be an inadequate representation of the total viral population in that sLT. Taken together, my data suggest that the nature of HIV-1 in the sLTs may be more complex than currently appreciated.

Degree

PhD

College and Department

Physical and Mathematical Sciences; Chemistry and Biochemistry

Rights

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