Retrovirus Updates

Blower, S.M., et al “A Tale of Two Futures: HIV and Antiretroviral Therapy in San Francisco” Science. January 28, 2000. Vol 287 (650-653)

Currently 30% of the San Francisco gay community are HIV infected.  50% of these individuals are taking combination ART (antiretroviral therapy consiting of three or more drug regimens including recently developed protease inhibitors and/or nonucleoside reverse transcriptase inhibtors).  Two models have been developed to examine rates of HIV infection and averting acquired immunodeficiency deaths in the San Francisco gay community.

Findings from 1996-1997 (when ART became readily available), have shown a drammatic decrease in the San Francisco AIDS death rate.  Although the clinical usuage of ART has been shown to reduce the rate of infection, these gains have been offset by an increase in risky behavior.  Consequently, maximization of both prevention and treatment programs should combine drug treatments with effective behavioral intervention programs.

HIV-1 infection" Proc R Soc Lond B Biol Sciences 1999 Dec 22;266(1437): 2523-30

One of the phenotypic differences between strains of human immundeficiency virus type I (HIV-1) has to do with the ability to cause target cells to form large multinucleated bodies known as syncytia.  There are two types of phenotypes according to this characteriation: syncytium-inducing (SI) and non-syncytium-inducing (NSI).  NSI strains are usually present throughout infection, while SI strains are typically seen at the beginning of the infection and near the onset of AIDS.  The late emergence of SI strains is known as phenotypic switching.  The purpose of this paper is to analyze the factors that lead to phenotype switching and contribute to the dynamics of disease progression.

The dynamics of the experiment found that the emergence of SI strains is crucially dependant on the population of active, HIV-specific CD4+ T-cells. Results indicate that this population of cells decays slowly, and once it falls low enough the SI virus emerges.

Rodman TC, Sullivan JJ, et al. "The Human Uniqueness of HIV: Innate Immunity and the Viral Tat Protein" Human Immunology. 60(8): 631-9, 1999 August.

The human innate system of natural antibodies includes two variations that are reactive with a specific sequence of the HIV Tat protein.  The human-typical pattern of innate/adaptive reactivity with HIV Tat protein is shared by chimpanzees, but not by other mammals tested in the study (monkeys, rabbits, and mice).  This characteristic potentially links the syndrome of AIDS fostered by a human-unique genetic characteristic, which accelerates the progression of HIV infection to the state of AIDS.

The significance of the Tat protein is shown in the pathogenic sequence of HIV infection by its role in cell attachment and entry of the virus.  Evidence from the in vitro study indicates that Tat participates in viral internalization and activation of inernal viral replication.  These functions have been shown to be dependant on the presence of "two natural epitopes of IgM antibodies that are present in all normal human and chimpanzee sera, but not present in other normal mammals".

Khorasanizadeh S. et al. "Solution Structure of the Capsid Protein from the Human T-cell Leukemia Virus Type I" Journal of Molecular Biology. 291(2): 491-505, 1999 Aug. 13.

The solution structure of the capsid protein (CA) from the human T-cell leukemia virus type one (HTLV-1) has been detemined by NMR methods.  The domains are structurally similar to the "N-terminal core and C-terminal dimerization domains, respectively, of HIV-1 and equine infectious anemia virus (EIAV) capsid proteins, although several important differences exist.  In particular, the hydrophobic resides near the major homology region are partially buried in HTLV-1."  The most surprising find of this research was that the HTLV-1 virus is monomeric, even at high protein concentrations, may be "attributed to the oxidation state of conserved cysteine residues in the C-terminal domains."

Bennet, Julie M., Steve Kaye, Neil Berry, et al. "A quantitative PCR method for the assay of HIV-1 provirus load in peripheral blood mononuclear cells" Journal of Virological Methods v.83 (1999) 11-20

The use of highly active antiretroviral therapies (HAART) to treat HIV-infected patients frequently results in the long-term suppression of plasma virus RNA loads below levels detectable by current assays.  The measurement of provirus DNA load in peripheral mononuclear cells provides a means to monitor the efficacy of drug treatment and the decline in reservoirs of latent virus.  A PCR method was developed to monitor viral clearance patterns in patients who were administered HAART.

There was found to be only one shortcoming in the experiment.  "Unlike plasma RNA loads which have a prognostic value in predicting disease progression, the relationship between PBMC provirus load and disease progression is less well defined."  Otherwise, the relationship between absolute provirus loads in asymptomatic patients and disease prognosis has yet to be fully established.

Chun TW and Fauci AS "Latent reservoirs of HIV: Obstacles to the eradication of virus". Proceedings of the National Academy of Sciences of the United States of America. 96(20):10958-61, 1999 September 28.

The suppression of plasma viremia in HIV-infected individuals recieving HAART has resulted in a highly beneficial clinical effect and a dramatic decrease in the date rate attributable to AIDS.  Nonetheless, peristent HIV virus reservoirs within latently infected, resting CD$+ T cells can give rise to infectious HIV upon stimulation.  This hidden "pocket" of virus is a major challenge against the complete eradication of virus.  Recent developnments that have shown to further reduce the presence of virus in-vitro include the use of intermittent leukin (IL)-2 in combination with continuous HAART.  Other developments include the use of intermittant infusions of immuno-enhancing cytokines (IL-2,4,6), thymic transplantation, bone marrow transplantation, and postinfection, HIV-specific vaccinations (which are currently being tested).

An SF, Groves M, Giometto B, et al. "Detection and localisation of HIV-1 and RNA in fixed adult AIDS brain by polymerase chain reaction/ in situ hybridization technique". Acta Neuropathol (1998) 98:481-487.

In the brain of patients with AIDS, HIV-1 is found in a productive form in mononuclear cells.  One question that has arisen is whether HIV can be localized in cells other than those of monouclear lineage.  By using PCR, gene amplification can be performed and used to study the prevalence of HIV in neural tissue.  In this study, the brain tissue from five adult AIDS patients was used.  Five of them showed evidence of HIV encephalitis, and five did not show any abnormality.

PCR revealed that HIV-1 DNA was present in all pf the HIVe cases and three in the normal group.  HIV-1 DNA from the positive patients was found in the "microglia, macrophages, perivascular cells, multnucleated giant cells, and in the CD68-negative cells".  Some these cells were identified as endothelial cells, astrocytes, and oligodendrocytes.  These results confirm infection of endothelial cells and other glial cells and give clues about the route of entry of virus into the central nervous system and about the pathogenesis of the disease.

Lawn, Stephen D., Beverly D. Roberts, et al. "Cellular Compartments of Human Immunodeficiency Virus Type I Replication In Vivo: Determination by Presence of Virion-Associated Host Proteins and Impact of Opportunistic Infection." Journal of Virology. January 2000. p. 139-145

Analysis of cell-free virus purified from plasma of patients with HIV-1 infection suggested that in thsoe with an opportunistic infection, viral replication occured in activated lymphocytes.  Interestingly, there was also significant replication in activated macrophages in those patients with untreated pulmonary tuberculosis; in addition to lymphocytes, the macrophage cellular pool may serve as an important source of cell-free HIV-1 in patients with opportunisitc infections that lead to macrophage activation.

Using a "immunomagnetic capture technique", the researchers were able to distinguish between macrophage-derived and lymphocyte-derived HIV-1.  Detection was based upon cell-type-specific host antigens incorporated into the viral envelope.  The findings from this report indicate that approximately 10% of HIV-1 virus, taken from a patient who developed active TB, was found to be macrophage derived.  This differs from previous studies that speculated less than 1 percent of cell-free HIV-1 is derived from macrophages.

Hazuda Daria J., Peter Felock, Mark Witner, et al. "Inhibitors of Strand Transfer That Prevent Integration and Inhibit HIV-1 Replication in Cells." Science Vol. 287 January 28, 2000

Integrase is essential for human immunodeficiency virus--type I (HIV-1) replication; however, potent inhibition of the isolated enzyme in biochemical assays has not shown antiviral activity consistent with the inhibition of integration.  In this report, diketo acid inhibitors of HIV-1 integrase were studied for their potential antiviral activity.  Th antiviral activity of these compounds have been attributed to the inhibition of one of the two catalytic functions of integrase, strand transfer.

By altering the kinetics of strand transfer, it was found that diketo acids bias the formation of replication-defective products and inhibit HIV repliction.  Mutations proximal to the integrase active site "residues engender resistance to the virus and isolated enzyme, establishing the diketo acids as the first biologically validated inhibitors of integration."

Medina, Daniel J., Peter P. Tung, et al "Use of recombinant viruses to assess the pattern of early human immunodeficiency virus breakthrough infection in the presence of stavudine." Journal of Gneral Virology. (1999), 80, 2361-2367.

Cell lines were infected with replication-defective recombinant retroviruses and subjected to stavudine (d4T).  Cells which were infected despite the presence of d4T were isolated and subjected to infection other retroviruses [replication competent HIV, replication defective HIV, or replication-defective recombinant murine retroviruses].  This study demonstrated that a heterogeneity of cell types hosting in vivo HIV infection maybe a valid model for studying the cellular mechanisms that contribute to HIV breakthrough during the natural progression of the disease.

This study has also shown that early HIV breakthrough infection in vitro in the presence of d4T is not solely a consequence of infection with virus that is genetically resistant to d4T.  As with AZT, "infection with drug-sensitive virus is a major mechanism of infection early after the introduction of the drug in vitro."  Further analysis of these mechanisms is required to understand prophylaxis strategies that should be implemented in an effort to eliminate or prolong the suspension of viable HIV.