AIDSWEEKLY Plus, 5 August 1996
Daniel J. DeNoon, Senior Editor

This unresolved question looms large in the quest for an HIV vaccine.

"It's the virus, stupid," says David Ho of New York's Aaron Diamond Research Center.

If so, an ideal HIV vaccine would elicit immune responses - neutralizing antibodies and/or cytotoxic lymphocytes (CTLs) - that directly attack the virus.

"Host factors are critical determinants of the resistance to pathogens and of the subsequent clinical outcome," says Giuseppe Pantaleo of the National Institute of Allergy and Infectious Diseases, Bethesda, Maryland.

If so, a vaccine or immunotherapy should specifically enhance helpful immune responses while attenuating those exploited by the virus.

Ho and Pantaleo debated this issue during a plenary session of the XI International Conference on AIDS, held July 7-12, 1996 in Vancouver, British Columbia, Canada.

The formal statement of the debate was "Resolved: That viral factors and not host factors are the primary determinants of pathogenesis." Ho argued in favor of this proposition; Pantaleo, against.

Ho began the debate by noting that he and Pantaleo agree on the facts, but differ on emphasis. The central fact that they agree on, he said, is that HIV is the etiologic agent of AIDS.

"There is no doubt that HIV causes AIDS, Peter Duesberg notwithstanding," Ho said.

He briefly outlined recent breakthrough research into the dynamics of HIV infection. These studies have shown that the battle between HIV and the immune system reaches a steady state about nine months after infection.

During this clinically latent period of equilibrium, there is a constant high level of viral replication, with some 10 billion viral particles produced each day and with half of all productively infected cells lost each day.

Ho argued that it is the level of viremia set during this equilibrium period that is the most important determinate of disease progression.

He pointed to the landmark study by University of Pittsburgh researcher John W. Mellors (Science, 1996;272:1124,1167; see AIDS Weekly, March 4, 1996) in which blood samples from participants in the Multicenter AIDS Cohort Study (MACS) were evaluated for viral burden.

"Only 8 percent of patients with the lowest viral load progressed to AIDS," Ho observed. "But 67 percent of patients with the highest viral load progressed to AIDS."

This setpoint of viremia, Ho said, is established by two factors:

• The size of the initial viral inoculum. Macaque monkeys inoculated with small amounts of SIV had low-level viremia and slow disease progression, while those inoculated with large amounts of SIV had high-level viremia and rapid disease progression.
• The viral phenotype. "Bad virus - bad outcome," Ho said. He noted that individuals infected by HIV strains with the syncytia-inducing (SI) phenotype - those that induce lethal cell clumping - have the highest viral loads. Moreover, the recently discovered fusin co-receptor for HIV does not work for HIV strains with a non-syncytia-inducing (NSI) phenotype.

Ho noted that nef-deleted vaccine strains of SIV are non- pathogenic because they replicate poorly, not because the immune system is better able to handle them.

Ho admitted that host factors play a role, particular host genetics with regard to human leukocyte antigen (HLA) types and cellular resistance to HIV, age (infants and the elderly do worse), and underlying medical conditions (such as coinfection with tuberculosis).

"Nevertheless, on balance it is the constant replication of HIV that serves as the engine to drive the pathogenesis of AIDS," he concluded.

Pantaleo opened his argument by noting that host factors influence resistance to a wide variety of bacterial and viral pathogens. Malaria, toxoplasmosis, leishmaniasis, trypanosomiasis, mycobacterial infection, and listeriosis are all diseases in which disease outcome depends on host susceptibility.

A specific host immune response, pathogen-specific CTLs, are extremely important in the control of lymphocytic choriomeningitis, influenza, cytomegalovirus infection, and hepatitis B.

With regard to HIV, Pantaleo said, several host factors are known to influence the course of disease:

• An individual's MHC genotype.
• An individual's cytokine response influences the degree of immune activation, which in turn affects the level of viral load and the subsequent course of infection.
• The ability of an individual's CD4 cells to resist HIV infection.
• The quality of the immune response varies among individuals.

"The genetic background of the susceptible host strongly modulates resistance to intracellular pathogens," Pantaleo said. "Resistance to infection and the severity of disease is modulated by the immune response."

The NIAID researcher pointed to animal studies showing that genetic modulation of the immune response affects:

• The induction of immune responses, i.e., antigen presentation and processing. MHC class I and II, transport- associated protein, and LMP and Bcg/lty/Lsh genes modulate this phase of the immune response.
• The selection and maturation of specific immune responses, particularly the selection of the T-cell receptor (TCR) repertoire. TCR, cytokine, and cytokine-receptor genes modulate this phase of the immune response.
• The effector phase of the immune response, e.g., CTL activity. NOS2, nuclear-resistance-associated macrophage protein (Nramp), pfp, Fasl, and Fas genes modulate this phase of the immune response.

With regard to TCR repertoire, Pantaleo announced unpublished study results showing that different patterns of TCR V(beta) expansion directly affect the number of CD4(+) T cells lost during the steady-state stage of HIV disease.

Three different patterns of V(beta) expansion were seen:

• In the type 1 pattern, mobilization of a restricted, monoclonal TCR repertoire led to the most rapid loss of T cells.
• In the type 2 pattern, mobilization of a more diverse, oligoclonal TCR repertoire led to a 30 percent less rapid loss of T cells than in the type 1 pattern.
• In the type 3 pattern, mobilization of a broad, polyclonal TCR repertoire led to 62 percent and 73 percent less rapid loss of T-cells than in the type 2 and type 1 patterns, respectively.

With regard to the Mellors data linking disease progression to levels of viremia, Pantaleo observed that these data did not account for individual differences in the crucial first six months of infection.

"Qualitative differences in immune response and not the level of viremia is the determinant of the rate of progression of HIV disease," Pantaleo concluded.

In rebuttal, Ho again stressed that he did not dispute Pantaleo's data.

"Obviously it takes two to tango, the virus and the host," he said. "But if you see HIV infection as a speeding locomotive, host factors only affect the speed of the train. HIV is the engine."

Ho reduced his argument to a simple set of equations.

"No HIV, no AIDS," he said. "Attenuate HIV and you attenuate disease. Constant HIV replication leads to constant CD4 [T-cell] destruction. Increased replication leads to fast [disease] progression; decreased replication leads to slow progression."

Given the last word, Pantaleo noted new research showing that specific C-C cytokines may play a role in resistance to HIV.

He also pointed to new findings that ironically came from Ho's coworkers at the Aaron Diamond AIDS Research Center, Nathaniel Landau and Richard Koup.

These findings showed that the CC CKR5 co-receptor for HIV is defective in some individuals who remain uninfected despite exposure to HIV.

"We must complement antiviral therapy with immune-based therapies," Pantaleo said.

During a subsequent press conference, Ho seemed to agree.

"We need to drive hard to find the correlates of immune protection so we can develop a vaccine," he said. "I anticipate a strong push in this direction."

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