The are some interesting problems relating to HIV reproductive kinetics that are posed by the data in a paper in The Journal of Experimental Medicine (JEM), Volume 190, Number 6, September 20, 1999 841-850. The authors report that approximately 19 cells are newly infected during logarithmic growth of HIV from cells that are not depleted.
The quantitation of HIV particles produced from a productively infected cell, 103 virions per cell, by Dimitrov et al., Journal of Virology, 67: 2182-2190, 1993 was studied using laboratory adapted strains of HIV grown in cell lines. Virion production of the same order of magnitude would seem be necessary to sustain both the proposed direct cytopathogenicity of the budding virus and the generation of a sufficiently large population of virions per cycle to account for the depletion of CD4+ cells, 5.4 X 109 CD4+ lymphocytes per day ( Ho et al., Nature, 373: 123126, 1995). This assumes that there are at least 1.0 X 106 CD4+ cells infected with replication competent virus (Chun et al. Nature, 387: 183-188, 1997), 103 virions produced per productively infected cell, and that 100% of these virions are able to initiate another round of infection. The data in the JEM paper would suggest far fewer infectious virions, albeit from cells not depleted. Also, Dimitrov et al. have found that of 109 viral particles only one viral particle in 103 to 104 are infectious.
These numbers seem not to add up to a direct cytopathic effect of HIV in depleting CD4+ cells. Taken together with the work of Tinkle et al., the progressive depletion of CD4+ lymphocytes is more likely due to the pathogenic effects of accessory genes or other factors, rather than the direct cytopathic effect of budding virions from productively infected cells; suggesting a therapeutic strategy directed at accessory gene product inactivation. Further, in HIV infected individuals without a Thymus gland,..."HIV-1 infection did not preclude either peripheral CD4+ T-cell rises or clinical responses after antiretroviral therapy." These data imply an extra-thymic site involved in T-cell neogenesis.
Much remains to be solved regarding HIV pathogenesis and basic Immune System function; a need for accelerated development and clinical trials of a live/attenuated vaccine, and treatment strategies to replace the current mix of highly toxic drugs of questionable effacacy.
Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection The capacity of HIV-1 to establish latent infection of CD4+ T cells may allow viral persistence despite immune responses and antiretroviral therapy. Measurements of infectious virus, and viral RNA, in plasma and of infectious virus, viral DNA and viral messenger RNA species in infected cells all suggest that HIV-1 replication continues throughout the course of infection. Uncertainty remains over what fraction of CD4+ T cells are infected and whether there are latent reservoirs for the virus. The authors show here that during the asymptomatic phase of infection there is an extremely low total body load of latently infected resting CD4+ T cells with replication-competent integrated provirus (<107 cells). The most prevalent form of HIV-1 DNA in resting and activated CD4+ T cells is a full-length, linear, unintegrated form that is not replication competent. The infection progresses even though at any given time in the lymphoid tissues integrated HIV-1 DNA is present in only a minute fraction of the susceptible populations, including resting and activated CD4+ T cells and macrophages.