Earlier assays of HIV replication and burden in the blood originally led researchers to believe that there was minimal viral replication throughout much of the course of HIV infection. Now, with more sensitive detection methods, it has been shown HIV is a chronic viral infection with measurable viral replication at all stages of disease. Unlike other viral infections, it now appears that HIV is never completely latent within an infected host, although at any given time most infected cells are not replicating virus. This implies either that a few chronically infected cells are manufacturing most of the virus measured, or that virus cycles rapidly through CD4+ T cells in short lytic infectious bursts.
How can either mechanism survive the apparently vigorous initial immune response? Very early on in HIV infection the immune system mounts a potent, multipronged attack on the virus; starting, it seems, with a cell-mediated response which is joined soon after by a humoral response, including the development of neutralizing antibodies. How does HIV persist and replicate at such high levels in an apparently immunocompetent host? In a related question, if HIV, a cytopathic virus with a tropism for CD4+ cells, is so successful at replicating at high levels right under the nose of the immune system, why is the course of HIV disease so often protracted, variable, and slow?
These questions raise the issue of which cells and tissues serve as reservoirs for HIV. (Although the recent lymph node work has shown virions attached to FDC processes, no one is implying that the FDCs are producing HIV - it most be coming from elsewhere.) Several researchers postulated a central role for the macrophage in the mechanism of viral persistence. One individual went as far as to say that HIV infection is a monocyte/macrophage disease. Some researchers report that the macrophages of primates who develop retroviral immune dysregulation (such as humans with HIV and rhesus macaques with SIV) are infected with these viruses, while primates which do not become sick (chimpanzees with HIV or African green monkeys with SIV) do not experience macrophage infection (others dispute this).
This, if true, implies that to cause disease, HIV or SIV must replicate in both CD4+ T cells and in macrophages. Still other mammalian retroviral diseases depend on dysregulating multiple arms of the immune system (e.g., MAIDS is a T cell dependent B cell disorder). Recent studies have suggested that macrophage-tropic, non-syncytium-inducing strains are selectively transmitted in the passage of HIV infection from one person to another. Once transmission occurs, HIV may use the macrophage as a "Trojan Horse" to disseminate itself throughout the body and as a reservoir of heavy viral production. Indeed, some studies report large numbers of viral particles localized almost exclusively with intracellular vacuoles in macrophages, with little or no virus detected at the plasma membrane. With little virus at the surface of the cell, the infected macrophage may be able to produce large amounts of virus without being "seen" by the immune system. Release of infectious virus and infection of other macrophages and T-cells can occur upon some event that perturbs macrophage function. Other immune cells, such as skin Langerhans cells and blood dendritic cells, may play a role in fostering viral persistence as well, though further research here is required.
Clearly, the immune system is able to control HIV replication to some extent for some period of time, which accounts for the slow progression of the disease in most cases, yet it is not able to eradicate it once infection has taken hold. The researchers interviewed stressed the need for studies of the natural history and pathology of HIV infection to elucidate the mechanisms of viral persistence. We need to know where HIV goes when it enters the body, where and how it hides from the immune system, what cells is it killing, and what cells are producing virus.
Events in the Host Life Cycle