The Role of the Cell Cycle in HIV-1 Infection

Summary

Infection of quiescent lymphocytes with human immunodeficiency virus type 1 (HIV-1) does not result in production of progeny virus. We have previously reported that although HIV-1 can enter quiescent lymphocytes with high efficiency, the reverse transcription process does not go to completion. This results in a viral genome which is composed partly of viral RNA and partly of viral DNA. If a mitogenic signal is applied shortly after infection to a cell harboring such a structure, reverse transcription can go to completion and progeny virus will be produced. However, this partially reverse transcribed structure is extremely labile, and the efficiency of virus rescue decreases rapidly, with increasing times between infection and activation. Our laboratory is using inhibitors of cell activation to identify at which stage of the cell cycle this block to reverse transcription occurs. We have found that agents that arrest the cell in the late G₁ phase of the cell cycle do not alter the ability of the virus to complete reverse transcription. However, agents that inhibit activation of the cell by blocking transition through G₁ prevent completion of reverse transcription. It thus appears that immunosuppression of the target cell may be a means of preventing productive infection of the cell.

We have also been using the severe combined immunodeficient mouse implanted with human tissue (SCID-hu) as an in vivo model to study HIV-1 pathogenic properties. When human fetal thymic implants in these animals are infected by HIV-1, profound depletion of CD4-bearing human thymocytes is seen. The depletion appears to initially be more pronounced in the immature CD4/CD8 double-positive thymocyte subset than in the more mature CD4+/CD8- subset. The reason for this preferential cell death is currently under investigation; however, this suggests that factors involved in cell differentiation may play a role in the pathogenic process.