AIDSWEEKLY Plus, Monday, 31 March 1997
Daniel J. DeNoon, Senior Editor

HIV vaccines containing cytotoxic lymphocyte (CTL) epitopes tailored to an individual's genetic makeup could prevent, or at least delay, AIDS, two new studies suggest.

The studies define for the first time the nature of protective CTL responses against HIV - and also precisely show how the virus evades these responses.

In an editorial accompanying the published results in the journal Nature Medicine, Daniel Zagury of Pierre and Marie Curie University, Paris, France, said that the findings could be used to develop a novel approach to creating an AIDS vaccine ("A Naturally Unbalanced Combat," Nature Med, 1997;3(2):156-7).

"Volunteers would ideally be immunized with various HIV immunodominant peptides corresponding to their particular HLA [human leukocyte antigen] phenotype in order to elicit memory CTLs exhibiting multiple anti-HIV specificities," Zagury wrote. "Such vaccines together with antiviral drugs and other biotherapeutic strategies targeting immunosuppression/cytokine dysregulation should be key weapons capable of driving the immune defense in favor of the host."

Since the beginning of the quest for an AIDS vaccine, researchers have complained that they were shooting in the dark, lacking crucial information about exactly which immune responses could offer protection against HIV. The two new studies help illuminate this target.

In the first of the breakthrough studies, Persephone Borrow of The Scripps Research Institute and colleagues performed a detailed molecular analysis of the anti-HIV CTL responses of a single patient (WEAU) followed from primary HIV infection through progression to AIDS ("Antiviral Pressure Exerted by HIV-1-Specific Cytotoxic T Lymphocytes (CTLs) During Primary Infection Demonstrated by Rapid Selection of CTL Escape Virus," Nature Med, 1997;3(2):205-11).

The patient was first tested 35 days after infection - and 15 days after onset of symptoms - via a single homosexual encounter with a person identified by DNA analysis as the source of transmission.

Plasma viremia peaked between 20 and 23 days following onset of symptoms, but declined rapidly thereafter. This decline coincided with the development of a strong CTL response directed against a single epitope at HIV gp160 amino acids 30-38. Soon thereafter, a broader CTL response developed.

Nevertheless, by 30 to 44 days following symptom onset, CTL escape mutants could be detected. These mutants had a single amino-acid change at gp160 position 31 which permitted escape from the patient's HLA-B44-restricted CTL.

The mutant strains completely replaced the original virus by day 136 following symptom onset, at which time plasma viremia began to increase. But this increase was not explosive: the patient had already developed CTL responses to several new viral epitopes (gp160[aa111-860], Gag, Pol, and Nef).

"Viral evolution to the amino acids 30-38 escape variant would likely have occurred even more rapidly, and plasma virus titers reached higher levels, had not CTL responses directed against other viral gene products developed," Borrow et al. suggested.

The shift to weaker CTL epitopes, however, may have signalled the end of viral containment for this patient, who had a rapid rate of disease progression.

Preliminary results from a second patient - also a rapid progressor - showed a similar pattern of viral escape from an early monospecific CTL response.

"The events we report here in patient WEAU are thus not unique and may in fact prove to represent a mechanism that HIV-1 commonly uses to evade control by the early antiviral immune response," Borrow et al. wrote. "The results presented here provide the first direct demonstration of the substantial and biologically relevant pressure exerted by the early CD8(+) CTL response on HIV-1 replication in vivo."

The authors suggested that their findings have direct implications for both prophylactic and therapeutic HIV vaccines.

"One aim of HIV-1 vaccines should thus be to elicit strong CTL responses against multiple codominant viral epitopes," they wrote.

In the second study, Oxford researcher Philip J.R. Goulder and colleagues first analyzed CTL responses from an HIV infected subject (dubbed "007") with the HLA-B27 phenotype, which has been linked to nonprogression to AIDS.

Subject 007 had a monospecific CTL response to the p24 Gag[263-272] epitope. Eleven years after infection, his CD4(+) T lymphocyte count dropped to below 100 cells/(micro)L. At this time, a viral mutant (K2M6) appeared, and over the course of a year, this mutant completely replaced the wild- type virus. Viral titers increased steadily.

Goulder et al. then studied five more HIV(+) people with the HLA-B27 phenotype. All had a strong CTL response to the same Gag epitope as subject 007. This was the dominant or single CTL response in three of the five new subjects.

HIV from another subject, 025, developed the same K2M6 escape mutation as seen in subject 007.

"The appearance in donor 025 of this K2M6 variant coincided with a decline in the CD4 count from 200 cells/(micro)L to 90 cells/(micro)L and a rapidly rising viral load (83,235 to 881,948 RNA copies/ml over 36 months)," Goulder et al. reported ("Late Escape from an Immunodominant Cytotoxic T-Lymphocyte Response Associated with Progression to AIDS," Nature Med, 1997;3(2):212-217).

The researchers concluded that in asymptomatic seropositive individuals with the HLA-B27 phenotype, dominant CTL responses are directed against the Gag 263-272 epitope. This response may be so strong as to exclude all other anti- HIV CTL responses.

In contrast, CTL responses in people with the HLA-B8 phenotype tend to be more broad and variable. HIV in such individuals tend to develop epitope mutations even in the context of low viral load.

"The identification of HLA-B27 as the HLA class I molecule most closely associated with nonprogression in HIV infection, and HLA-B8 as associated with rapid progression, may be related to these differences in immune response," Goulder et al. suggested.

The researchers concluded that the increase in HIV viremia that signals the onset of AIDS may be the result of overgrowth of CTL escape mutants.

"Escape from CTL responses may play a more important role in the progression of HIV infection than has been recognized," they wrote.

The corresponding author for the Borrow et al. study is Persephone Borrow, Department of Neuropharmacology, Division of Virology, The Scripps Research Institute, 10550 North Torrey Pines Road (IMM-6), La Jolla, California 92037.

The Borrow et al. study was supported by NIAID grants AI 37430, AI 35467, AI 09484, and MH 51519; the HIV Correlates of Human Immune Protection Contract N01-A1 45218; and by the University of Alabama Center for AIDS Research (AI 27767) and the Birmingham Veterans Administration Medical Center.

The corresponding author for the Goulder et al. study is Philip J.R. Goulder, Nuffield Department of Clinical Medicine and Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DU, United Kingdom.

The Goulder et al. study was supported by the U.K. Medical Research Council and the Wellcome Trust.

The corresponding author for the editorial accompanying these studies is Daniel Zagury, Universite Pierre et Marie Curie, Laboratoire de Physiologie Cellulaire, 75252 Paris Cedex 05, France.

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