Nef-Deleted HIV Appears To Be Weaker—can a vaccine or therapy be developed?

In the June 3 1999 issue of The New England Journal of Medicine (V 340,Num 22, p 1715) Jennifer Learmont and others published their findings regarding a small group of individuals in the Sydney Blood Bank Cohort. These individuals received blood through transfusion from an HIV-infected person, but remain HIV-negative or with low viral load and a-symptomatic 14-18 years later. This story has been well known for a number of years. The authors findings suggest that the strain of HIV that these individuals were infected with had a gene which had certain identified portions missing. They were shown to be infected with a strain of HIV-1 (sub-type B) with a conserved deletion in the nef-LTR region of their HIV. SIV strains of HIV lacking the nef gene have been shown to be weaker in macaque monkeys and to replicate less well in vivo than strains with nef intact.

The authors suggest that this missing part is the reason why 5/13 individuals are HIV sero-negative, and 7/8 have low (median: 645 to 2850 copies/ml) or undetectable viral load (<200 copies/ml). The blood donor’s viral load has started to increase to a higher range of about 20,000 copies/ml. The proportion of CD4 lymphocytes has declined significantly in 5 individuals. Three of the 4 with detectable HIV RNA in plasma had significantly declining CD4 counts, as compared with no declines in the 3 with undetectable HIV RNA. The authors suggest that nef-deleted HIV can cause immunological damage and "must have highly potent mechanisms for eliminating CD4 lymphocytes". But they maintain their study data supports previous suggestions that a drug inhibiting the action or actions of the Nef protein might substantially ameliorate the progression of HIV-1 infection.

Strains of HIV like the nef-deleted one described in this article, or other strains with additional mutations have been suggested as the basis of live attenuated vaccines to prevent infection with wild-type strains of HIV. The authors said the problem is that low-level HIV replication is required to develop and sustain a protective immune response. But in the case of live attenuated SIV vaccines studied in macaque monkeys, the available evidence suggests that even with low-level replication, substantial immunodeficiency developed in a number of infected animals. But it appears that the decline in CD4s may take many years to become evident.

In a commentary of this study published in the same edition of The NEJM written by Gary Nabel and Kathleen Collins, they raise concerns about the use of live attenuated HIV strains for vaccines. They support this by referring to 3 persons in the Sydney Bank Cohort who had evidence of "virological progression", and to 1 person in the cohort who died of of PCP after receiving immunosuppressive therapy for systemic lupus erythematosus. But in reading the full published article in NEJM, Learmont suggests that 2 of these 3 persons died of causes unrelated to HIV. A fourth person’s first HIV serological result, on February 2, 1996, "was weakly positive according to enzyme-linked immunosorbent assay with an indeterminate Western Blot, and subsequent results have been similar". HIV-DNA sequences consistent with the Sydney Blood Bank Cohort HIV-1 quasispecies have been found in genomic DNA from PBMCs (peripheral blood mononuclear cells) amplified by nested PCR. The person remains symptom free, with a viral load below detection and a "borderline but stable CD4 count of 480. In addition, this person has a host genotype associated with slow progression to HIV—a heterozygous mutation of the CCR5 gene. Nabel and Collins maintain that "if large populations of uninfected persons were given virus, there would almost certainly be unacceptable risk". This subject has been controversial as many people have said a study in humans should proceed testing this vaccine approach while a number of others have opposed such studies. Starting such a study appears stalemated.

Nabel and Collins go on to say "if the virus could be further attenuated without loss of immunogenicity, this approach might be feasible. The main question is whether adequate attenuation would eliminate the efficacy of such a vaccine". They suggest it might be useful to develop drugs that target nef but so far researchers have been unable to develop such drugs.