HIV This Week

Jlizi A, Edouard J, Fadhlaoui-Zid K, Frigi S, Debré P, Slim A, Theodorou I, El Gaaied AB, Carpentier W. Identification of the CCR5-Delta32 HIV resistance allele and new mutations of the CCR5 gene in different Tunisian populations. Hum Immunol. 2007 ;68(12):993-1000.

Polymorphisms in some chemokine receptor genes are associated with susceptibility to and progression of human immunodeficiency virus-1 (HIV-1) infection . Most mutations detected in the CC-chemokine receptor 5 (CCR5) gene are specific to different populations. In this study, Jlizi and colleagues focused on polymorphisms of the CCR5 coding region in three healthy populations from Tunisia, corresponding to a cosmopolitan population from Tunis, and two isolated Berber populations. In addition to the CCR5-Delta32 deletion, eleven single nucleotide polymorphisms were detected. Some of these point mutations were associated with the same genotype and even the same haplotype. The (L55Q-C101X), I124, V131F, T143N, A159V, I237, T239A and G301R alleles have not been described previously, whereas the CCR5-Delta32, L55Q, A335V and Y339F variants have already been reported in the literature. The distribution and frequency of these variants were different among the three groups studied, a result in agreement with the mosaic genetic structure of the Tunisian population. To determine whether these alleles affect HIV-1 transmission, the authors compared allele frequencies between healthy and HIV-1 infected individuals from Tunis. The frequency of the CCR5-Delta32 variant was significantly different between the two groups, leading us to conclude that this mutation might confer protection against HIV infection in Tunisian populations.

Editors’ note: CCR5-Delta32 produces a truncated protein affecting CCR5 gene expression and function and is associated with resistance to HIV infection and slower disease progression. In this study, CCR5-Delta32 was the most frequent variant found in healthy individuals (frequency 0.034) but not found at all in infected individuals. Furthermore, the CCR5-Delta32 mutant was present in the Tunisian population at its highest frequency among Arab countries. The authors speculate that even this low frequency of genetic difference may combine with male circumcision, religious customs, and social norms to explain the low incidence of HIV infection in Tunisia. Additional studies are needed to confirm this interesting hypothesis.

Transmission of HIV-1 via intercellular connections has been estimated as 100-1000 times more efficient than a cell-free process, perhaps in part explaining persistent viral spread in the presence of neutralizing antibodies. Such effective intercellular transfer of HIV-1 could occur through virological synapses or target-cell filopodia connected to infected cells. Here Sowinski and colleagues report that membrane nanotubes, formed when T cells make contact and subsequently part, provide a new route for HIV-1 transmission. Membrane nanotubes are known to connect various cell types, including neuronal and immune cells, and allow calcium-mediated signals to spread between connected myeloid cells. However, T-cell nanotubes are distinct from open-ended membranous tethers between other cell types, as a dynamic junction persists within T-cell nanotubes or at their contact with cell bodies. The authors also report that an extracellular matrix scaffold allows T-cell nanotubes to adopt variably shaped contours. HIV-1 transfers to uninfected T cells through nanotubes in a receptor-dependent manner. These data lead us to propose that HIV-1 can spread using nanotubular connections formed by short-term intercellular unions in which T cells specialize.

Editors’ note: Transfer of HIV-1 via nanotubes that create physical connections between T cells minimize exposure of the virus to extracellular antibodies, permitting it to escape an important immune defence. This may help explain the virulence and pathogenicity of HIV-1; it also suggests a new avenue for drug targets.