AIDSWEEKLY Plus, Monday, 11 August 1997
Daniel J. DeNoon, Senior Editor

Understanding the immunology of the HIV-1 gp120 envelope glycoprotein is essential for the development of an AIDS vaccine, argues a team of leading AIDS researchers.

The team, including David D. Ho, Martin Markowitz, and John P. Moore of the Aaron Diamond AIDS Research Center (ADARC), studied HIV antibody responses to HIV-1 Env and Gag antigens in several cohorts of HIV infected individuals.

They found, in agreement with previous studies, that only long-term nonprogressors (LTNP) mount effective anti-gp120 antibody responses. In contrast, most people infected with HIV mount a massive, but almost completely ineffective response to the antigen.

"These factors provide a sobering perspective on developing vaccines based on neutralizing antibody induction," wrote ADARC researcher and lead author James M. Binley and colleagues. "Thus, it is urgent to discover how best to bring forth the full immunogenic potential of gp120."

Binley et al. reported and discussed the implications of their findings in the Journal of Virology ("Differential Regulation of the Antibody Responses to Gag and Env Proteins of the Human Immunodeficiency Virus Type 1," J Virol, 1997;71:279-2809).

The researchers investigated one of the paradoxes of humoral immune responses to HIV: that the loss of or failure to develop anti-Gag antibody responses is associated with disease progression, while retention of anti-Env antibodies has little if any effect.

They analyzed Gag (anti-p24 and anti-p17) and Env (anti- gp120 and anti-gp41) antibody responses in four groups of patients: LTNPs, AIDS patients, acute seroconverters, and first-time recipients of an HIV-1 protease inhibitor.

Studies of acute seroconverters showed that:

* Both the size and kinetics of anti-Env and anti-Gag responses are independently regulated.

* The decline in anti-Gag responses indicative of poor prognosis sometimes occurs soon after infection - within six months in two of the patients studied. "Whatever (irreversible?) immunological events lead to an inability to generate a strong, sustained anti-Gag response, they can occur rapidly," Binley et al. wrote. "This finding emphasizes the importance of starting antiviral therapy early."

* Measurable changes in plasma viremia are unrelated to increases or decreases in anti-Env or anti-Gag antibody titers.

Similarly, antibody titer was unrelated to dramatic changes in plasma viremia seen in chronically infected patients treated with the protease inhibitor ritonavir. One hopeful finding, however, was that partial restoration of lost anti-p24 response was seen after only a few weeks of treatment in one patient. When therapy failed in this patient due to emergence of drug-resistant virus, anti-p24 responses did not decline for several months despite rebound of plasma viremia.

Binley et al. rejected the hypothesis that anti-Gag antibodies disappear due to the formation of antibody complexes with free p24 antigen.

"It is not obvious why anti-gp120 would not be subject to the same fate," they wrote. "Overall, it is hard to believe that free p24 available in plasma for antibody complexing greatly exceeds free gp120; both are probably present in the picogram/milliliter to low nanogram/milliliter range."

They also dispensed with the idea that the loss of anti- Gag antibodies is related to insufficient Gag antigen to stimulate antibody production, noting that there is always a quantity of circulating nonparticulate p24 and that the billion or so infected T cells destroyed each day would release enough p24 to provoke an immune response.

"Our preferred explanation, as others have also argued, is that the presence of anti-Gag antibodies is simply a surrogate marker for an efficiently functioning immune system," Binley et al. concluded. "T-cell help is required for the efficient presentation of antigens to B cells, and perhaps also to maintain antibody secretion from terminally differentiated plasma cells. Thus, the anti-Gag loss as disease progresses could be due to the inexorable destruction of CD4(+) T-helper cells through HIV-1 infection."

Why, then, does the ineffective anti-Env response persist? Binley et al. suggested that even though it does not resemble classical T-independent antigens, gp120 may not require T-cell help to generate antibody. They cite several lines of evidence:

* CD4 binding of gp120 could help present the antigen to B- cell antigen receptors.

* Virions carry p24 internally, while they present gp120 on their surfaces. This could allow differential presentation of the antigens to B cells.

* gp120 is a very unusual antigen. "Thus it may be that the anti-gp120 response is atypical because of the atypical nature of gp120 itself," Binley et al. suggested.

* Env antigens are glycosylated while Gag antigens are not. Glycosylated antigens may be preferentially aided by non- helper T cells.

With regard to this latter point, the authors noted that dendritic cells - important antigen-presenting cells - bind glycoproteins. This could affect the emergence of neutralizing antigens and help explain HIV neutralizing anti- gp120 antibodies lag about six months behind the appearance of gp120 variants.

"If gp120 (or virus) trapped on follicular dendritic cells in lymphoid tissue and only slowly exchanging with plasma virus is the antigen that generates neutralizing antibodies, then it is inevitable that this response will be mostly directed against a viral strain that disappeared from the plasma tens of HIV-1 generations ago, for there are 150 such generations per year," Binley et al. wrote.

"The emergence of neutralizing antibody-resistant variants in plasma may have little to do with escape from selection pressure but may be the inevitable consequence of a viral replication rate so rapid that it is drastically out of kinetic equilibrium with the antigen presentation machinery of the humoral immune system."

The researchers calculated that HIV-1 chronically stimulates production of antibodies that are enormously inefficient at neutralizing the virus. Chronic HIV-1 infection can result in anti-gp120 plasma concentrations of more than 1 mg/ml.

"Perhaps HIV-1 infection stimulates permanently an acute- phase type of antibody response, leading to sustained secretion of antibodies to HIV-1," they speculated. "This massive anti-gp120 production may be necessary to have even a minimal effect on neutralization-resistant primary viruses; even rare reagents with potent neutralizing activity against primary viruses protect SCID-Hu mice from infection only when present at plasma concentrations of >100 (micro)g/ml."

Binley et al. noted that long-term nonprogressors sustain high-level anti-gp120 responses despite having undetectable plasma levels of gp120. In contrast, volunteers vaccinated with gp120 receive up to 10(7) times more of the antigen than circulates in the plasma of LTNPs yet have only transient antibody responses.

"It is no surprise that natural HIV-1 infection induces a better antibody response than gp120 vaccination," Binley et al. concluded. "But it can be inferred that gp120 injection intramuscularly is not the most efficient way to present it to the immune system. Thus, it would seem desirable to gain more understanding of the natural mechanisms of gp120 presentation to enable better immunization strategies to be devised."

This study was supported by the Aaron Diamond Foundation, by NIH grant RO1 AI36082, and by NIH contract AI45218 (Correlates of HIV Immune Protection; Principal Investigator S. Wolinsky).

The corresponding author for this study is John P. Moore, Aaron Diamond AIDS Research Center, 455 1st Ave., 7th Floor, New York, New York 10016. Phone: (212) 725-0018. Fax: (212) 725-1126. Email: jmoore@adarc.org.

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