AIDSWEEKLY Plus; Monday, December 28, 1998
Daniel J. DeNoon, Senior Editor
This is the question that looms over the Sydney Blood Bank Cohort (SBBC): a group of people infected with a very special strain of HIV via blood transfusions from an infected donor (see Vaccine Weekly, March 17, 1997 and January 20, 1997). What makes these patients' HIV so special is that it has a defective nef gene. This is the same gene that, when deleted to create prototype live-virus AIDS vaccines, offers the most complete protection against virulent challenge of any vaccine approach yet tested.
All of the SBBC members have been healthy and without symptoms of AIDS for 13 to 17 years. Indeed, a new study shows that many of these patients still have robust HIV specific cytotoxic T-lymphocyte (CTL) activity similar to that seen in animals protected by prototype vaccines.
But recent follow-up of these patients suggests that at least some may be showing signs of disease progression.
"Our recent follow-up of these individuals suggests that slow disease progression may be occurring in some members with detectable viral replication," wrote Wayne B. Dyer of the Australian Red Cross Blood Service and colleagues. "We suggest that a potential vaccine candidate would require further attenuation than that in the natural SBBC viral strain."
The statement is the first published acknowledgement of data revealed during a debate over human trials of a live, attenuated HIV vaccine at the 1998 World AIDS Conference (see AIDS Weekly, August 24, 1998). Harvard's Ruth Ruprecht, who has found that attenuated nef- deleted simian immunodeficiency virus (SIV) can be pathogenic, argued against the human trials and revealed that members of the Sydney Blood Bank Cohort have declining T-cell counts. She called on Jennifer Learmont of the Australian Red Cross Blood Service to confirm this.
"A few [cohort members] have always had low detectable virus load: it's not a re-emergence," Learmont said. "but you're correct in saying that their CD4 counts are slipping. Some are below 500 cells/(micro)L."
Learmont and colleagues have submitted a paper on these data for publication. Meanwhile, Dyer et al. focus on the positive implications of the SBBC data for live, attenuated HIV vaccines.
"Despite 13 to 17 years of infection with an attenuated strain of HIV-1, strong CTL responses were detected in four of seven SBBC patients; two of these four individuals had very low and undetectable viral loads, respectively," they wrote.
Dyer et al. published their findings in the Journal of Virology ("Strong Human Immunodeficiency Virus (HIV)-Specific Cytotoxic T- Lymphocyte Activity in Sydney Blood Bank Cohort Patients Infected with nef-Defective HIV Type 1," J Virol, 1999;73(1):436-43).
Protection against pathogenic SIV in macaque monkeys vaccinated with nef-deleted SIV has been ascribed to the strong SIV-specific CTL responses seen in these animals.
"Our observations may suggest that a similar outcome may be anticipated if this vaccine strategy is attempted in humans," Dyer et al. suggested.
Moreover, none of the patients have sexually transmitted the nef- defective HIV-1 strain with which they are infected. And Dyer et al. noted that elderly cohort members retain strong anti-HIV immunity.
Fears that attenuated virus will revert to pathogenic form appear unfounded. The researchers have found that the nef deletions in virus isolated from SBBC members have actually increased in size.
Nevertheless, the finding that nef deletion may not be enough to attenuate a live-HIV vaccine is troubling. More fully attenuated virus may not replicate well enough to elicit protective immunity.
"Regardless of whether a prophylactic HIV vaccine contains a live attenuated or otherwise modified strain of HIV-1, this study emphasizes that an attenuated strain of HIV-1 is capable of inducing sustained CTL responses, but whether such responses are capable of protecting against a wild-type HIV-1 challenge remains to be determined," Dyer et al. concluded.
This work was supported by the Macfarlane-Burnet Research Syndicate, the Medical Research Council (U.K.), Aaron Diamond AIDS Research Center funds, and an NIH grant.
The corresponding author for this study is Wayne B. Dyer, Australian Red Cross Blood Service - NSW, 153 Clarence St., Sydney, NSW 2000, Australia. Phone: 61 2 9229 4557. Fax: 61 2 9229 4251. Email: <wdyer@arcbs.redcross.org.au>.
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