The Role of Biomedical Research in Combating AIDS: Proceedings of the 56th Meeting of the Advisory Committee to the Director, NIH

infected at any given time, mechanisms other than direct lymphocyte depletion
must account for such broad immunological effects such as a selective
depletion of a subset of T4 cells or a CD4-positive nonlymphoid cell,
critical to the propagation of the entire T-cell pool, become involved.
Experiments throughout the country have suggested that very early lineage
cells are susceptible to infection.
The discussion focused on another elusive problem--the qualitative
defects in the T4 cells present in latent or low-level chronic infection.
Several possible explanations were presented, including a cytopathic effect on
a very small subset of T4 positive cells and a noncytopathic infection of CD4 -positive cells.
In addition, one participant noted that while the monocyte can be
infected with HIV, the ensuing cytopathic effect is relatively low. Thus,
monocytes can function as a reservoir that carry the virus and freely
disseminate it. Then, in response to an activation signal, they can shed
virus infecting CD4-positive lymphocytes or brain cells.
Finally, the mechanisms of conversion from latency to productivity were
addressed. Conversion factors include mitogens and antigens, as well as
physiological signals in a normal setting. Collaborators such as Drs. Tom
Folks, Malcolm Martin, Arnold Rabson, and others have demonstrated that an
HIV-infected cell line can be induced to express virus by cytokines that are
secreted in the process of normal immunological responses. Dr. Rabson and his
group showed that this occurs by a transactivating mechanism.
The committee reviewed what is known about the immunopathogenic
mechanisms. The virus can enter the body in either a cell-free or a cellassociated form. The portals of entry are understood, but the mechanism of
the initial infection is not. Ultimately, the T4 cell and/or the monocyte
macrophage are infected and can remain so for a long period of time without
immunosuppression. Opportunistic bursts of infection can be due to other
viruses, other cofactors, or normal physiological stimuli such as cytokines.
The ultimate common denominator is that the monocyte macrophage itself can
either bring the virus to the brain or to other T-cells. The T-cell itself
requires an activation signal and, once activated, results in productive
infection leading to cell destruction, lymphopenia, immunosuppression, and
eventually opportunistic infection.
Advances and Next Steps in Understanding the Pathogenesis and Natural History
of AIDS
Richard T. Johnson, M.D.
Eisenhower Professor of Neurology
Johns Hopkins School of Medicine
Dr. Johnson stated that HIV infection is now known to have two primary
targets, the immune system and the central nervous system (CNS). Earlier, the
neurological involvement was undiscovered, as was the cause of the progressive

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