Detachment of human immunodeficiency virus type 1 from germinal centers by blocking complement receptor type 2.

After the transition from the acute to the chronic phase of human immunodeficiency virus (HIV) infection, complement mediates long-term storage of virions in germinal centers (GC) of lymphoid tissue. The contribution of particular complement receptors (CRs) to virus trapping in GC was studied on tonsillar specimens from HIV-infected individuals. CR2 (CD21) was identified as the main binding site for HIV in GC. Monoclonal antibodies (MAb) blocking the CR2-C3d interaction were shown to detach 62 to 77% of HIV type 1 from tonsillar cells of an individual in the presymptomatic stage. Although they did so at a lower efficiency, these antibodies were able to remove HIV from tonsillar cells of patients under highly active antiretroviral therapy, suggesting that the C3d-CR2 interaction remains a primary entrapment mechanism in treated patients as well. In contrast, removal of HIV was not observed with MAb blocking CR1 or CR3. Thus, targeting CR2 may facilitate new approaches toward a reduction of residual virus in GC.

Serum HIV-1 RNA levels compared to soluble markers of immune activation to predict disease progression in HIV-1-infected individuals.

We assessed the value of HIV-1 RNA level compared to soluble immune activation markers, namely neopterin, beta2-microglobulin and soluble TNF receptor 75 (sTNFR-75), to predict the change in the number of CD4+ T cells over a 1-year period, the development of AIDS, and survival (median follow-up 54 months). The study population comprised a cohort of 47 individuals for the analysis of the change in CD4+ T cells and survival (20 died), and a subgroup of 31 individuals with a baseline CD4+ T cells above 200 x 10(6)/l for the development of AIDS (11 developed AIDS). HIV-1 RNA was measured from stored sera by quantitative PCR. The CD4+ T cell count obtained at study entry strongly correlated with baseline serum HIV-1 RNA levels (r=-0.47), and to a lesser extent with neopterin (r=-0.41) and beta2-microglobulin (r=-0.29). The percentage change in CD4+ T cells over a 1-year period correlated with HIV-1 RNA levels (r=-0.32, p=0.03), however, stronger correlations were found for neopterin, beta2-microglobulin and sTNFR-75 (r=-0.51, r=-0.41, r=-0.42; p< 0.01). No progression to AIDS or death was observed in individuals with baseline HIV-1 RNA levels below 20,000 copies/ml (10 of 31 and 15 of 47 individuals, respectively). A Cox's proportional hazard model to predict AIDS revealed that HIV-1 RNA, the change in CD4+ cells over a 1-year period and sTNFR-75 levels independently predict AIDS; the change in CD4+ cells, the absolute CD4+ T cell count and neopterin were jointly significant to predict death. All results were adjusted for nucleoside monotherapy. In conclusion, to improve the predictive power, quantitation of HIV-1 RNA as a 'natural history marker' may be supplemented by measurement of sTNFR-75 for 'early'-stage disease progression and neopterin for 'late'-stage disease progression.

Distribution of human endogenous retrovirus HERV-K genomes in humans and different primates.

The distribution of the human endogenous retrovirus (HERV)-K genome was investigated by Southern-blot analyses using a HERV-K-env DNA probe. With the exception of one DNA-sample, obtained from a Chinese individual in whom an amplification of HERV-K was detected, Southern-blot analyses yielded identical hybridization patterns with DNA from peripheral blood lymphocytes of 37 normal healthy blood donors, with DNA from six tumor cell lines, or with 23 DNA samples prepared from various carcinoma tissues. To elucidate whether the integration of HERV-K genomes into the primate lineage occurred as a single event or as an integration with later expansion, we further examined the evolutionary history of HERV-K by Southern blot analyses with DNA samples from different primate species. We detected HERV-K genomes in Macaca mulatta and Macaca silenus, which represent Old World monkeys, but not in prosimians (Galago demidovii) and New World monkeys, represented by Saguinus fuscicollis, Saguinus oedipus, and Callithrix iacchus. Thus, we assume that the infection of the primate lineage with HERV-K had occurred after the divergence of New World and Old World monkeys, but before the evolutionary expansion of large hominoids. In contrast to the apparent lack of HERV-K-env sequences in DNA from tissue of the New World monkey Saguinus oedipus (cotton-top marmoset), we found HERV-K-DNA in the B95-8 cell-line, which is a Saguinus oedipus leukocyte cell-line, immortalized in vitro by Epstein-Barr virus (EBV) and cultivated in human cells. It may be speculated that HERV-K-DNA or HERV-K-particles were introduced into these cells during in vitro transformation with EBV.