|Genetic Variability: Implications for the Development of HIV Vaccines (UNAIDS, 1996, 16 p.)|
The genetic variability of HIV-1 strains has also been correlated with in vitro growth characteristics of the virus. Syncytia-inducing (SI) viruses can replicate in immortalized T-cell lines, inducing syncytia of the target cells. Non-syncytia-inducing (NSI) viruses are unable to replicate in immortalized T-cell lines, but grow in primary CD4+ cells (T lymphocytes and macrophages) [7,41-47]. The biological properties of HIV-1 are largely determined by genetic variation in the env gene, in particular in the V3 loop. Point mutations which lead to substitutions by positively charged amino acids at specific positions in the V3 loop, and which result in an overall increase of its positive charge, strongly correlate with SI properties of the virus [43,44]. In addition, other regions in the env gene, including V1, V2, C4, and the gp41 transmembrane region are also being investigated as potential genetic determinants of the viral biological properties [48,49]. Interestingly, despite substantial genetic variation between different subtypes, the genetic determinants of biologically important domains are largely conserved among the known subtypes .
Although mixtures of SI and NSI virus variants are found at any point in time within a single infected individual, the earliest virus population observed following HIV infection is generally of the NSI phenotype. However, very early in infection, before seroconversion, a selective amplification of SI variants may occur, although it is rapidly controlled and maintained at relatively low levels during the asymptomatic course of the infection. However, the late stages of infection are characterized by the emergence of SI variants, which then take over the NSI virus population [45,50].
Of potential importance for vaccine development is the observation that NSI and SI viruses differ in their susceptibility to neutralizing antibodies, probably due to a different configuration of their outer envelope glycoprotein. More specifically, the V3 loop seems to be relatively inaccessible to V3-specific neutralizing antibodies among NSI isolates, whereas it is more accessible among SI strains . The present generation of HIV candidate vaccines was developed based on SI viruses, and in immunized animals or human volunteers, the neutralizing antibodies that they induced are mostly directed against V3 loop linear determinants. This could explain the reported failure of these candidate vaccines in inducing neutralizing antibodies against NSI "clinical" isolates of the virus. This led to speculation that effective HIV vaccines must induce antibodies capable of neutralizing "clinical" isolates, perhaps by inducing antibodies directed against conformational epitopes present in multimeric gp120 molecules. However, chimpanzees immunized with monomeric gp120/MN candidate vaccines have been protected from a challenge with a closely related "clinical" strain (SF2), even when the sera from the immunized animals failed to neutralize the virus (D. Francis, personal communication). It remains an open question if protection can be equally achieved against SI and NSI viruses.