Mechanisms of HIV non-progression; robust and sustained CD4+ T-cell proliferative responses to p24 antigen correlate with control of viraemia and lack of disease progression after long-term transfusion-acquired HIV-1 infection

<p>Abstract</p> <p>Background</p> <p>Elite non-progressors (plasma viral load <50 copies/ml while antiretroviral naive) constitute a tiny fraction of HIV-infected individuals. After 12 years follow-up of a cohort of 13 long-term non-progressors (LTNP) identified from 135 individuals with transfusion-acquired HIV infection, 5 remained LTNP after 23 to 26 years infection, but only 3 retained elite LTNP status. We examined the mechanisms that differentiated delayed progressors from LTNP in this cohort.</p> <p>Results</p> <p>A survival advantage was conferred on 12 of 13 subjects, who had at least one host genetic factor (HLA, chemokine receptor or TLR polymorphisms) or viral attenuating factor (defective <it>nef</it>) associated with slow progression. However, antiviral immune responses differentiated the course of disease into and beyond the second decade of infection. A stable p24-specific proliferative response was associated with control of viraemia and retention of non-progressor status, but this p24 response was absent or declined in viraemic subjects. Strong Gag-dominant cytotoxic T lymphocyte (CTL) responses were identified in most LTNP, or Pol dominant-CTL in those with <it>nef</it>-defective HIV infection. CTL were associated with control of viraemia when combined with p24 proliferative responses. However, CTL did not prevent late disease progression. Individuals with sustained viral suppression had CTL recognising numerous Gag epitopes, while strong but restricted responses to one or two immunodominant epitopes was effective for some time, but failed to contain viraemia over the course of this study. Viral escape mutants at a HLA B27-restricted Gag-p24 epitope were detected in only 1 of 3 individuals, whereas declining or negative p24 proliferative responses occurred in all 3 concurrent with an increase in viraemia.</p> <p>Conclusion</p> <p>Detectable viraemia at study entry was predictive of loss of LTNP status and/or disease progression in 6 of 8, and differentiated slow progressors from elite LTNP who retained potent virological control. Sustained immunological suppression of viraemia was independently associated with preserved p24 proliferative responses, regardless of the strength and breadth of the CTL response. A decline in this protective p24 response preceded or correlated with loss of non-progressor status and/or signs of disease progression.</p

Phenotype and envelope gene diversity of nef-deleted HIV-1 isolated from long-term survivors infected from a single source

<p>Abstract</p> <p>Background</p> <p>The Sydney blood bank cohort (SBBC) of long-term survivors consists of multiple individuals infected with attenuated, <it>nef</it>-deleted variants of human immunodeficiency virus type 1 (HIV-1) acquired from a single source. Long-term prospective studies have demonstrated that the SBBC now comprises slow progressors (SP) as well as long-term nonprogressors (LTNP). Convergent evolution of <it>nef </it>sequences in SBBC SP and LTNP indicates the <it>in vivo </it>pathogenicity of HIV-1 in SBBC members is dictated by factors other than <it>nef</it>. To better understand mechanisms underlying the pathogenicity of <it>nef</it>-deleted HIV-1, we examined the phenotype and <it>env </it>sequence diversity of sequentially isolated viruses (n = 2) from 3 SBBC members.</p> <p>Results</p> <p>The viruses characterized here were isolated from two SP spanning a three or six year period during progressive HIV-1 infection (subjects D36 and C98, respectively) and from a LTNP spanning a two year period during asymptomatic, nonprogressive infection (subject C18). Both isolates from D36 were R5X4 phenotype and, compared to control HIV-1 strains, replicated to low levels in peripheral blood mononuclear cells (PBMC). In contrast, both isolates from C98 and C18 were CCR5-restricted. Both viruses isolated from C98 replicated to barely detectable levels in PBMC, whereas both viruses isolated from C18 replicated to low levels, similar to those isolated from D36. Analysis of <it>env </it>by V1V2 and V3 heteroduplex tracking assay, V1V2 length polymorphisms, sequencing and phylogenetic analysis showed distinct intra- and inter-patient <it>env </it>evolution.</p> <p>Conclusion</p> <p>Independent evolution of <it>env </it>despite convergent evolution of <it>nef </it>may contribute to the <it>in vivo </it>pathogenicity of <it>nef</it>-deleted HIV-1 in SBBC members, which may not necessarily be associated with changes in replication capacity or viral coreceptor specificity.</p

Pathogenicity and immunogenicity of attenuated, nef-deleted HIV-1 strains in vivo

In efforts to develop an effective vaccine, sterilizing immunity to primate lentiviruses has only been achieved by the use of live attenuated viruses carrying major deletions in nef and other accessory genes. Although live attenuated HIV vaccines are unlikely to be developed due to a myriad of safety concerns, opportunities exist to better understand the correlates of immune protection against HIV infection by studying rare cohorts of long-term survivors infected with attenuated, nef-deleted HIV strains such as the Sydney blood bank cohort (SBBC). Here, we review studies of viral evolution, pathogenicity, and immune responses to HIV infection in SBBC members. The studies show that potent, broadly neutralizing anti-HIV antibodies and robust CD8+ T-cell responses to HIV infection were not necessary for long-term control of HIV infection in a subset of SBBC members, and were not sufficient to prevent HIV sequence evolution, augmentation of pathogenicity and eventual progression of HIV infection in another subset. However, a persistent T-helper proliferative response to HIV p24 antigen was associated with long-term control of infection. Together, these results underscore the importance of the host in the eventual outcome of infection. Thus, whilst generating an effective antibody and CD8+ T-cell response are an essential component of vaccines aimed at preventing primary HIV infection, T-helper responses may be important in the generation of an effective therapeutic vaccine aimed at blunting chronic HIV infection

Longitudinal Analysis of Human Immunodeficiency Virus Type 1 nef/Long Terminal Repeat Sequences in a Cohort of Long-Term Survivors Infected from a Single Source

We studied the evolution of human immunodeficiency virus type 1 (HIV-1) in a cohort of long-term survivors infected with an attenuated strain of HIV-1 acquired from a single source. Although the cohort members experienced differing clinical courses, we demonstrate similar evolution of HIV-1 nef/long-terminal repeat (LTR) sequences, characterized by progressive sequence deletions tending toward a minimal nef/LTR structure that retains only sequence elements required for viral replication. The in vivo pathogenicity of attenuated HIV-1 is therefore dictated by viral and/or host factors other than those that impose a unidirectional selection pressure on the nef/LTR region of the HIV-1 genome

Viral Phenotypes and Antibody Responses in Long-Term Survivors Infected with Attenuated Human Immunodeficiency Virus Type 1 Containing Deletions in the nef and Long Terminal Repeat Regions▿

The Sydney Blood Bank Cohort (SBBC) consists of eight blood transfusion recipients infected with nef-attenuated human immunodeficiency virus type 1 (HIV-1) acquired from a single donor. Here, we show that viral phenotypes and antibody responses differ considerably between individual cohort members, despite the single source of infection. Replication of isolated virus varied from barely detectable to similar to that of the wild-type virus, and virus isolated from five SBBC members showed coreceptor usage signatures unique to each individual. Higher viral loads and stronger neutralizing antibody responses were associated with better-replicating viral strains, and detectable viral replication was essential for the development of strong and sustained humoral immune responses. Despite the presence of strong neutralizing antibodies in a number of SBBC members, disease progression was not prevented, and each cohort member studied displayed a unique outcome of infection with nef-attenuated HIV-1

Phenotype and envelope gene diversity of -deleted HIV-1 isolated from long-term survivors infected from a single source-0

<p><b>Copyright information:</b></p><p>Taken from "Phenotype and envelope gene diversity of -deleted HIV-1 isolated from long-term survivors infected from a single source"</p><p>http://www.virologyj.com/content/4/1/75</p><p>Virology Journal 2007;4():75-75.</p><p>Published online 16 Jul 2007</p><p>PMCID:PMC1939844.</p><p></p>roduction in culture supernatants was measured by RT assays. Values shown are means from duplicate infections. Error bars represent standard deviations. Results are representative of two independent experiments using cells obtained from different donors

Phenotype and envelope gene diversity of -deleted HIV-1 isolated from long-term survivors infected from a single source-4

<p><b>Copyright information:</b></p><p>Taken from "Phenotype and envelope gene diversity of -deleted HIV-1 isolated from long-term survivors infected from a single source"</p><p>http://www.virologyj.com/content/4/1/75</p><p>Virology Journal 2007;4():75-75.</p><p>Published online 16 Jul 2007</p><p>PMCID:PMC1939844.</p><p></p>-1 infected PBMC and subjected to GeneScan analysis, as described in the Methods and elsewhere [41, 56]. (A) GeneScan sample files generated from amplified products. (B) Fraction of sequences with a given V1V2 nucleotide length, which was calculated from GeneScan sample files. Peaks and bars shown in red represent V1V2 amplimers from early viruses, and peaks and bars shown in blue represent V1V2 amplimers from late viruses. Similar results were obtained in two independent experiments