Lynn Morris

Human immunodeficiency virus type 1 (HIV-1) subtype C viruses with different coreceptor usage profiles were isolated from 29 South African patients with advanced AIDS. All 24 R5 isolates were inhibited by the CCR5-specific agents, PRO 140 and RANTES, while the two X4 viruses and the three R5X4 viruses were sensitive to the CXCR4-specific inhibitor, AMD3100. The five X4 or R5X4 viruses were all able to replicate in peripheral blood mononuclear cells that did not express CCR5. When tested using coreceptor-transfected cell lines, one R5 virus was also able to use CXCR6, and another R5X4 virus could use CCR3, BOB/GPR15, and CXCR6. The R5X4 and X4 viruses contained more-diverse V3 loop sequences, with a higher overall positive charge, than the R5 viruses. Hence, some HIV-1 subtype C viruses are able to use CCR5, CXCR4, or both CXCR4 and CCR5 for entry, and they are sensitive to specific inhibitors of entry via these coreceptors. These observations are relevant to understanding the rapid spread of HIV-1 subtype C in the developing world and to the design of intervention and treatment strategies.

Neutralizing antibodies represent an important component of immune control in many viral infections. In HIV‐1 infection, almost all individuals develop antibodies capable of neutralizing autologous viruses in vitro; however, the role of these antibodies in vivo still remains unclear. Their absence during the acute phase of infection, when the viral levels are brought under control, suggests they play a minor role in immune control and that cellular immune responses are more critical during this time. However, during chronic infection these antibodies may be important in preventing cell‐to‐cell spread and they still represent our best hope of providing sterilizing immunity (i.e., prevention of infection) by vaccination. Significant advances over the last few years in understanding the structure of the envelope glycoproteins have renewed interest in the role of neutralizing antibodies and the possibility that immunogens capable of stimulating a neutralizing antibody response can be developed.

The use of antiretroviral drug therapies in HIV-1 infected pregnant women and their infants has resulted in significant reductions in the rates of mother-to-child transmission of HIV-1. A number of drugs that target the reverse transcriptase enzyme have been tested either alone or in combination in short-course regimens tailored for use in developing countries. The drug of choice is nevirapine, which is cheap, easy to administer and highly effective even following a single dose to mother and child. However, this regimen is associated with the selection of mutations associated with drug resistance. While these mutations do not compromise the ability of nevirapine to prevent mother-to-child transmission there is some concern that they may compromise future treatment options. Here we review the current data on HIV-1 drug resistance mutations and what they might mean in terms of efficacy of antiretroviral therapies to prevent mother-to-child transmission.

Tuberculosis (TB) is the major opportunistic infection of HIV-infected patients in developing countries and is associated with activation of the immune system and increased HIV-1 expression. The aim of this study was to explore the biological properties of HIV-1 isolates from patients with active TB. Ten HIV-1 subtype C isolates were analyzed for biological phenotypes, using MT-2 cells, and for coreceptor usage, using coreceptor-transfected cell lines. All isolates were nonsyncytium inducing (NSI) in the MT-2 assay and replicated in CCR5-expressing cells. None of the isolates used CXCR4 or any of the minor coreceptors (CCR1, CCR2b, or CCR3) efficiently. Analysis of the V3 region showed that all isolates contained the GPGQ motif characteristic of subtype C and also had a sequence profile typical of NSI viruses. These data indicate that despite their advanced disease state, patients with TB harbor viruses that use the CCR5 coreceptor. It is possible that activation of monocytes and macrophages during TB infection results in the expansion of macrophage-tropic isolates that preferentially use CCR5.

The incidence of Kaposi’s sarcoma in South Africa is increasing in parallel with the human immunodeficiency virus type 1 epidemic. An 804 bp region in the ORF75 gene of 40 human herpesvirus-8 (HHV-8) isolates from South Africa was sequenced and the phylogenetic relationships were compared to published sequences. Nineteen strains clustered with subgroup B and 11 with subgroup A; however, the bootstrap values supporting these subgroups were not significant. Three strains grouped significantly with the C subgroup, while eight sequences did not cluster with any of the previously classified subgroups and were termed novel (N). The N subgroup differed from the A, B and C subgroups by DNA distances of 4·8, 4·2 and 4·5%, respectively, although within the N subgroup there was only 0·4% variation. The inclusion of this subgroup increased the number of previously described subgroup-specific polymorphisms from 17 to 47 over an 804 bp region. There was sufficient inter-subgroup genetic diversity for a single-strand conformational polymorphism assay to be used to identify them rapidly. Thus, based on analysis of the ORF75 gene, a unique HHV-8 subgroup, termed N, is present in South Africa, which accounts for 20% of circulating strains. Further studies are required to determine the degree of genetic divergence, distribution and pathogenic potential of this novel subgroup.