HIV Vaccines: Could Vaccine Alter Course of HIV Disease?

http://www.aegis.com/pubs/aidswkly/1996/AW960404.html

AIDSWEEKLY Plus, April 29, 1996 issue; Published by Charles Henderson, Publisher. Editorial & Publishing Office: P.O. Box 5528, Atlanta, GA 30307-0528 / Telephone: (800) 633-4931; Subscription Office: P.O. Box 830409, Birmingham, AL 35283-0409 / FAX: (205) 995-1588
Daniel J. DeNoon, Senior Editor

Whether HIV disease will rapidly progress or remain relatively stable is established very early in the course of infection, new studies confirm.

The new data identify stage-independent predictors of disease progression. Examination of these predictors in AIDS- vaccine recipients with breakthrough HIV infection should indicate whether the vaccine can change the course of disease.

"The ability to more carefully define the stage and rate of progression of HIV-1 disease could potentially assist preventive and therapeutic vaccine trial design by allowing balanced stratification of subjects," suggested researcher Michael T. Wong of Wilford Hall Medical Center, Lackland Air Force Base, Texas, and colleagues.

Wong et al. reported their findings in The Journal of Infectious Diseases ("Patterns of Virus Burden and T Cell Phenotype Are Established Early and Are Correlated with the Rate of Disease Progression in Human Immunodeficiency Virus Type 1-Infected Persons," J Inf Dis, 1996;173(4):877-887).

Wong et al. studied a cohort of 1,200 patients enrolled in the U.S. Air Force arm of the prospective Tri-Service Natural History Program. This program follows HIV infected patients in the U.S. military health-care system and periodically collects samples of plasma, serum, and peripheral blood mononuclear cells (PBMC).

The researchers identified 32 patients with rapid progression of HIV disease (defined as rapid decline in CD4(+) T-cell counts with progression to clinical AIDS) and 25 patients with stable disease (defined as constant or rising CD4(+) T-cell counts with no clinical disease).

All of these patients received intensive virological and immunological evaluations of samples collected over a four- year period. Evaluations included virus load in serum and PBMC, (beta)[2]-microglobulin, delayed-type hypersensitivity (DT 960429H) to recall antigens, HIV p24 antigen, and determination of CD4(+), CD8(+), natural killer (NK) cell, and gamma-delta T-cell subsets.

The resulting data were subjected to various univariate and multivariate statistical analyses.

"The contrast of rapid-progression and stable-progression populations indicates that regardless of progression rate or the compartment assessed, the pattern and magnitude of virus load is established early in HIV disease," Wong et al. found. "The magnitude is the single virologic feature that distinguishes the more rapid from the slower course of disease."

These findings support the "steady-state" hypothesis: that soon after HIV infection the virus and the immune system establish a dynamic equilibrium characterized by a plateau level of viral burden. Higher plateau levels are associated with more rapid progression to disease and death. Moreover, animal and human studies suggest that there is a certain threshold level for this plateau below which the immune system is able to eliminate the virus.

However, the current study is among the first to systematically evaluate phenotypic features of the cellular immune compartment over time.

Multivariate analysis showed that the major phenotypic predictors of the rate of disease progression were the markers CD3(+)CD4(+)CD28(+) and gamma-delta T-cell-receptor-bearing HLA-DR(+).

"In early HIV-1 infection, a constellation of high virus burden and in vivo costimulatory antigen and lymphocyte activation abnormalities is predictive of rapid disease course," Wong et al. concluded.

The proportion of CD4(+) and CD8(+) T cells lacking the CD28 costimulatory molecule predicted the rate of HIV progression but did not change during the course of infection.

"These CD28(-) cells, when stimulated via the T-cell receptor, would be expected to respond with anergy or apoptosis, ascribing a functional deficit to this phenotypically characterized determinant of rate," Wong et al. wrote.

"CD4(+) cells might be induced to become CD28(-) as a result of direct viral infection of the cell or contact of the cell membrane with suppressive viral products or as a consequence of HIV-influenced cytokine patterns or deranged regulatory cell suppression."

These findings confirm previous observations that the loss of "naive" unstimulated T-cell precursors is the hallmark of HIV disease.

"The loss of naive cells, through inadequate production, excessive stimulatin and conversion to memory cells, or both, could theoretically decrease the ability of CD4(+) cells to respond to new antigens or to broaden existing responses," Wong et al. suggested.

Another T-cell phenotype that did not change over time but which discriminated rapid from stable progressors (and both groups from normal controls) was the percentage of CD29(+)CD26(-)CD4(+) cells.

"CD26 (dipeptidyl peptidase IV) is physically associated with CD45 on T cells, has been associated with T-cell activation and CD3 phosphorylation, and identifies a T-cell subset reacting to soluble and recall antigens," Wong et al. noted. "Cross-sectional studies have found CD26 is decreased on T cells of HIV positive patients and suggest that CD4(+)CD26(-) cells are the main reservoir for HIV-1."

Finally, there is an increase in the percentage of T cells bearing the gamma-delta receptor soon after HIV infection - even before CD4(+) lymphocyte counts begin to decline. This proportion does not change over time, but its magnitude differentiates between rapid and stable disease.

"In most of the phenotypic subsets tested, those showing slow as well as rapid progression were significantly different from normal controls, demonstrating distinctive changes in immune subsets compared with uninfected subjects," Wong et al. concluded. "These observations suggest that those showing slow and rapid progression represent the ends of a continuous spectrum of severity of disease progression rather than discrete groups."

The researchers concluded that the optimal time to intervene in HIV disease would be soon after infection, before establishment of steady-state equilibrium.

They stressed the importance of determining whether the disease-stage-independent predictors of progression are altered in recipients of experimental HIV vaccines who suffer breakthrough HIV infections.

"The constancy of many of these markers over time, used as surrogates of outcome, could provide a greater power to identify treatment effects for a given sample size," Wong et al. suggested.

The corresponding author for this study is Michael T. Wong, Department of Infectious Diseases, Wilford Hall Medical Center, 2200 Bergquist Dr., Suite 1, Lackland Air Force Base, Texas 78236-5300.

Copyright (c) 1995 - Charles Henderson, Publisher. All rights Reserved. Permission to reproduce granted to AEGIS by Charles W. Henderson. Authorization to reproduce for personal use granted granted by C. W. Henderson, Publisher, provided that the fee of US$4.50 per copy, per page is paid directly to the Copyright Clearance Center, 27 Congress Street, Salem, Massachusetts 01970, USA.

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