Roger J Pomerantz; David L Horn


Nat Med. 2003;9(7) 

In This Article

1998: Recognition of HIV-1 Latency and Reservoirs; Restoration of Immune Function With HAART; Early Attempts at Eradicating HIV-1 Infection

The treatment of HIV-1 is complicated by the existence of tissue compartments and cellular reservoirs. Much of the virus in the central nervous system[46] and in semen[47,48,49] evolves independently of virus found in blood cells. Latently infected, resting CD4+ T lymphocytes[50,51] can survive for many years, and these lymphocytes can archive many quasispecies of virus that can re-emerge and propagate after the withdrawal of HAART. Macrophage populations can also express virus in HIV-1-infected individuals on virally suppressive HAART.[52] Moreover, HAART does not inhibit all viral replication;[53,54] low levels of viral replication occur 'cryptically' below the limits of clinical plasma viral load detection.

Viral latency and low-level viral replication in the presence of HAART have hindered attempts at eradication of HIV-1 from selected individuals who have undergone extensive protocols combining HAART, didanosine, hydroxyurea, CD3 murine monoclonal antibodies (OKT-3) and interleukin (IL)-2. IL-2 was added to one regimen to stimulate latent provirus.[55,56] In this case, the semen reservoir was effectively suppressed without evidence of viral rebound upon withdrawal of suppressive therapy, which had occurred elsewhere as measured by plasma viral load. This finding may have implications for infectivity and sexual transmission of HIV-1. Novel strategies combining new agents that enhance the immune response will likely lead to other improvements, with the short-term goal of eliciting clinical behavior similar to that of long-term HIV-1 nonprogressors (HIV-1-infected individuals that maintain normal immunity without requiring antiretroviral therapy). In some ways, one can now approach HIV-1 infection with an 'oncological paradigm'.[52] As such, initial HAART would represent induction therapy, whereas therapies to attack latent reservoirs and cryptic viral replication would represent approaches against residual disease. As we learn more about protected reservoirs or compartments and possibly sanctuary sites, as well as how to stimulate expression of virus in latently infected cells, we may come closer to our ultimate goal of eradication of HIV-1 in infected individuals.[57,58]

Another salutary effect of HAART is the restoration of immune function, which routinely occurs on long-term therapy and leads to the regeneration of robust CD4+ and CD8+ cellular responses to recall antigens.[59,60] This commonly results in the resolution of persistent opportunistic infections. The restoration of immune response has given way to dramatic patient care improvements, as doctors are now able to withdraw suppressive antimicrobial therapy for many opportunistic infections caused by such organisms as Pneumocystis carinii, Toxoplasma gondii, cytomegalovirus, Mycobacterium avium intracellular complex, Cryptococcus neoformansand Candida albicans.[61]