Berta Rodés

Differences in disease progression in a cohort of long-term non-progressors after more than 16 years of HIV-1 infection.

Background: It is unclear whether resistance to immunologic damage in long-term non-progressors (LTNP) will last indefinitely or whether it merely represents the extreme of a Gaussian distribution, and therefore progression will occur eventually. Patients and methods: A cohort of 19 LTNP was established in 1997. Plasma viraemia and CD4 cell counts were measured two to three times each year until 2003. Analyses of nef and vpr viral genes, CCR5 genotypes, co-receptor tropism, viral replication capacity, and immunological parameters were performed. Results: Twelve subjects (non-progressors, NP) showed stable CD4 cell counts over the 6-year follow-up, while seven (slow progressors, SP) showed a trend towards progressive CD4 cell depletion; however, only three SP experienced significant CD4 cell count declines. All SP had detectable plasma HIV-RNA (median 1118 copies/ml). In contrast, five of 12 NP had always undetectable viraemia. Only one patient showed a deletion in nef. The vpr R77Q change was recognized in seven patients. All patients were infected with R5 viruses. The virus replicative capacity was reduced in all tested individuals (range 5–93%). None of the patients was homozygous for the delta-32 CCR5 genotype, which was found in heterozygosis in three. CD8 T-cell activation was low in all but three individuals, all of whom had detectable viraemia and showed progressive CD4 cell depletion. Cytotoxic T lymphocyte responses were similar to those found in a control group of HIV progressors. Conclusions: A substantial proportion of LTNP show low-level virus replication and progressive loss of CD4 T cells over time. Progressive immunologic damage seems to be directly associated with some degree of virus replication and T-cell activation.

MUTATIONS AFFECTING THE REPLICATION CAPACITY OF THE HEPATITIS B VIRUS

Summary.  The genetic variability of the hepatitis B virus (HBV) encounters two compounding forces: a high viral copy number produced during active replication and the lack of proofreading activity in the HBV polymerase, resulting in a high mutational rate. A large pool of quasispecies is generated in which the fittest virus, i.e. the virus that replicates best, becomes the dominant species. Immune and antiviral selection pressures result in vaccine/immunoglobulin escape mutants and antiviral resistant variants. Viruses encoding changes associated with antiviral resistance often have reduced replication in vitro, but the accumulation of additional mutations helps restore viral fitness. These compensatory mutations may occur not only in the polymerase gene but also in other genes such as the overlapping envelope gene, the precore gene, or in regulatory regions such as the basal core promoter. In this report we aim to review the new findings that have appeared in recent months.

Long-term non-progressors display a greater number of Th17 cells than HIV-infected typical progressors

Interleukin 17 (IL17) secreting T (Th17) cells play a protective role against bacterial infections at mucosal surfaces. Recent reports show Th17 cells are depleted in the gut associated lymphoid tissue of HIV+ patients, but their role in HIV disease progression is not well understood. Expression of the IL17 receptor (IL17R) and the production of IL17 were compared between two groups of HIV patients with different disease progression (long-term-nonprogressors, LTNP and typical-progressors, TP). IL17R expression was similar in LTNP and TP, whereas Th17 cell number was greater in LTNP than TP (p=0.015). An inverse correlation between the plasma HIV-RNA and both IL17R expression and Th17 cell number was found (p=0.001 and p=0.002, respectively). The increased number of Th17 cells in LTNP could lead to a more preserved immune response against bacterial infections. As a result, lower microbial translocation could explain the reduced immune activation and slower disease progression seen in LTNP.

Evolution of the gp41 env region in HIV-infected patients receiving T-20, a fusion inhibitor.

T-20 belongs to a new family of antiretroviral drugs that inhibits HIV entry. Resistance may develop in vitro as result of changes within the GIV motif of the HIV-1 gp41. However, none of four individuals who failed treatment with T-20 selected those changes. One developed a change (G→V) at position 36 not previously described. Therefore, other changes in the env gene might be responsible for the loss of susceptibility to T-20 in vivo.

Risk of selecting K65R in antiretroviral-naive HIV-infected individuals with chronic hepatitis B treated with adefovir

Seven antiretroviral-naive HIV-infected individuals with chronic hepatitis B treated with adefovir for longer than 6 months were assessed. Using bulk population sequencing and a sensitive limiting dilution analysis, the selection of K65R or other resistance mutations did not occur in HIV, suggesting that adefovir can be confidently used as hepatitis B virus (HBV) therapy in HIV/HBV-co-infected patients who do not require antiretroviral therapy.

Quality control assessment of human immunodeficiency virus type 2 (HIV-2) viral load quantification assays: results from an international collaboration on HIV-2 infection in 2006.

ABSTRACT Human immunodeficiency virus type 2 (HIV-2) RNA quantification assays used in nine laboratories of the ACHIEV2E (A Collaboration on HIV-2 Infection) study group were evaluated. In a blinded experimental design, laboratories quantified three series of aliquots of an HIV-2 subtype A strain, each at a different theoretical viral load. Quantification varied between laboratories, and international standardization of quantification assays is strongly needed.

Mimotopes selected with antibodies from HIV-1-neutralizing long-term non-progressor plasma.

A promising approach to identify HIV‐1 vaccine candidates is to dissect the natural immune response against the virus in persons controlling the infection over decades without any antiviral therapy. Here we focus on a group of such persons, eight long‐term non‐progressors (LTNP), in which we proved the presence of broadly neutralizing antibodies against HIV‐1 in the plasma as very likely cause for their LTNP status. The aim of this study was to identify the epitopes for these neutralizing antibodies, as these should represent immunogens potentially able to elicit neutralizing antibodies upon vaccination. We screened random peptide phage libraries with plasma antibodies from eight LTNP. After several rounds of positive and negative selection, about 700 HIV‐specific mimotopes were sequenced. The mimotope sequences were analyzed for homology to HIV‐1 Env, in particular for their capacity to represent conformational epitopes on the surface of the gp120 structure using our software 3DEX. Related phage groups were analyzed for crossreactivity with the LTNP plasma by ELISA as well as for their capacity to induce HIV‐1‐neutralizing antibodies in mice. Based on this study interesting mimotopes can now be selected for further immunization studies.

Are Fusion Inhibitors Active against All HIV Variants

Genetic sequence alignment of the transmembrane region from HIV-1 group O and HIV-2 isolates was performed to examine their potential susceptibility to fusion inhibitors enfuvirtide (T-20) and T-1249. A high genetic diversity within the HRI and HR2 domains was found, which should compromise any antiviral effect of T-20 on HIV-2 and HIV-1 group O viruses. However, conserved sequences in the gp41 regions from HIV-1 group O involved in T-1249 susceptibility might result in a much broader antiviral effect of T-1249 on HIV-1 variants. In contrast, genetic diversity in those regions make unlikely any activity of these compounds on HIV-2.

The effect of antiretroviral therapy on HTLV infection.

No effective treatment for TSP/HAM has been described so far. Interventions with corticosteroids, plasmapheresis, interferon and, more recently, with antiretroviral drugs have been tried with poor results. The main HTLV replication mechanism is thought to be through clonal expansion of HTLV-infected cells, which excludes the involvement of the reverse transcriptase (RT) enzyme. However, a virological and clinical improvement has been noticed in HTLV-I carriers suffering from TSP/HAM receiving zidovudine or lamivudine. Herein, we describe the virological and clinical outcome in two TSP/HAM patients infected with HTLV-I treated with zidovudine plus lamivudine, and in two HTLV-II/HIV-1 co-infected patients receiving triple combinations including lamivudine. While, one TSP/HAM patient experienced a 2 log decrease in HTLV-I proviral load, an increase of 1 log was observed in another patient after several months of treatment with zidovudine plus lamivudine. The two HTLV-II/HIV-1 co-infected patients showed an initial increase in HTLV-II proviral load after beginning HAART followed by a slight decline a few months later. Plasma HIV-1 RNA fell to <50 copies/ml in both patients after beginning therapy. None of the four HTLV positive patients developed genetic changes at the conserved YMDD domain within their respective RT genes, which could be related to lamivudine resistance. No clinical improvement was observed in one TSP/HAM patient after more than 1 year on treatment with nucleoside analogues. The inhibition of the HTLV RT along with the cytostatic effect of some nucleoside analogues, including zidovudine, could reduce HTLV replication, and therefore reduce HTLV proviral load. The clinical consequences of this effect need to be further examined.

High rate of proV47A selection in HIV-2 patients failing lopinavir-based HAART.

We describe the emergence of the proV47A mutation in three out of five HIV-2-infected individuals failing lopinavir/ritonavir-based HAART. The appearance of such mutated variants resulted in high levels of phenotypic resistance to lopinavir, cross-resistance to indinavir, amprenavir, and hypersusceptibility to saquinavir. A search in HIV-2 databases revealed that proV47A is present in 8.6% of protease inhibitor (PI)-experienced patients but absent in all PI-naive patients. Its selection may be a common mutational pathway for developing resistance to lopinavir/ritonavir in HIV-2.