Our long term objective is to develop prevention and treatment strategies to block initial HIV infection and very early replication. We believe presentation of HIV by B cells may be an important and, until recently, overlooked source of infectious HIV at the time of initial exposure, and a major component of systemic dissemination from the gut during the hyperacute pre-seroconversion phase. Our unpublished studies indicate that normal B cells potentiate, to a remarkable and unexpected degree, macrophage derived R5 HIV infection within autologous PBMCs, perhaps by presenting cell-associated HIV in a highly efficient manner to susceptible CD4+ T cells and macrophages. Therefore, our immediate objectives are to 1) confirm the dominant role of normal B cells in promoting HIV replication in normal PBMCs, 2) identify the mechanism(s) of this B cell enhancement;3) characterize the HIV transmission potential for B cells to purified CD4+ T cells, monocyte derived macrophages (MDMs), and immature dendritic cells (iDCs). We hypothesize that: 1) In the absence of HIV specific Abs, normal B cells play a significant role in the initial stages of infection, via cell-cell contact presentation of virions to susceptible PBMC populations. 2) Contact dependent B cell potentiation of HIV infection in whole PBMC cultures reflects HIV binding to B cell surface membrane via DC-SIGN, CD40, LFA-1, and (in the presence of C3d) CD21. 3) Contact-dependent B cell presentation of HIV to purified autologous and allogeneic T cells, MDMs, and allogeneic DCs will be more efficient than cell free virus infection. This would be the first systematic evaluation of the phenomenon of B cell contact dependent HIV transmission using non-engineered virus and normal leukocytes in various pairings. It is the first attempt to demonstrate the importance of normal B cells for infection of PBMC cultures. This work has significance for understanding mechanisms and range of HIV transmission during initial exposure, hyperacute gut infection, and pre-seroconversion systemic dissemination. Since B cells are highly mobile through the spleen, liver, and lymphoid system, they represent excellent transporters of HIV from localized sites of production to distant niches of long term replication. These studies could suggest new therapeutic and preventive strategies against HIV infection, and might also point to B cell related genes as candidates for AIDS Resistance Polymorphisms.
Virion """"""""decorated"""""""" B cells are a relatively unstudied potential source of infectious HIV during initial exposure from blood or semen, and during the hyper acute infection of the gut, as well as during subsequent chronic HIV infection. Our studies have revealed a remarkable and surprising contribution of B cells to HIV replication in normal blood cells, and understanding the basis for this virus enhancing role may eventually help us block initial infection or better contain acute infection within the gut. In addition to treatment and prevention strategies targeted at HIV hitching a ride on B cells, our work will suggest new genes to consider as AIDS resistance factors.
