Effects of recombinant human growth hormone on HIV-1-specific T-cell responses, thymic output and proviral DNA in patients on HAART: 48-week follow-up

Background: Efficacious immune-based therapy in treated chronic HIV-1 infection requires the induction of virus-specific CD4+ T cells and subsequent maturation and maintenance of specific memory CD8+ T cells. Concomitant daily administration of recombinant human growth hormone (rhGH) with highly active antiretroviral therapy (HAART) was used in chronically infected patients with lipodystrophy in an attempt to reconstitute these virus-specific T-cell responses. Methods: Individuals with chronic HIV-1 infection on HAART were enrolled on a randomized, double-blinded, placebo-controlled study to receive rhGH therapy. We assessed HIV-1-specific proliferative CD4+ and interferon-gamma (IFN-γ)-producing CD8+ T-cell responses, quantified thymic output and proviral HIV-1 DNA at the following time points: baseline; after 12 weeks of rhGH therapy; at 24 weeks, after randomization into three groups [placebo weeks 12-24 (Group A), alternate-day dosing weeks 12-24 (Group B), and twice-per-week dosing weeks 12-24 (Group C)]; and at 48 weeks after all patients had received HAART alone for the final 24 weeks. Results: We found significant increases in both proliferative CD4+ and IFN-γ-producing CD8+ HIV-1-specific T-cell responses after daily administration of rhGH. This increase was focused on HIV-1 Gag-specific T-cell responses. Following subsequent randomisation into different dosing regimens, HIV-1-specific proliferative CD4+ T-cell responses declined in patients receiving less frequent dosing of rhGH, while virus-specific IFN-γ-producing CD8+ T-cell responses were maintained for longer periods of time. There was no significant change in thymic output and the cell-associated HIV-1 DNA remained stable in most patients. An increased anti-HIV-1 Nef-specific CD4+ T-cell proliferative response was correlated to a decrease in proviral load, and an increased HIV-1 Gag-specific IFN-γ-producing CD8+ T-cell response correlated with an increase in proviral load. Conclusion: The implication of these data is that daily dosing of rhGH with HAART, in addition to improving HIV-1-associated lipodystrophy, may reverse some of the T-lymphocyte dysfunction seen in most treated HIV-1-positive patients, in a dose-dependent manner. Such immune-based therapeutic strategies used in treated, chronic HIV-1 infection may enable the induction of virus-specific CD4+ T cells essential for the subsequent kick-start and expansion of virus-specific CD8+ T cells. © 2008 Herasimtschuk et al; licensee BioMed Central Ltd

Are Long-Term Non-Progressors Very Slow Progressors? Insights from the Chelsea and Westminster HIV Cohort, 1988–2010

Define and identify long-term non-progressors (LTNP) and HIV controllers (HIC), and estimate time until disease progression. LTNP are HIV-1+ patients who maintain stable CD4+ T-cell counts, with no history of opportunistic infection or antiretroviral therapy (ART). HIC are a subset of LTNP who additionally have undetectable viraemia. These individuals may provide insights for prophylactic and therapeutic development. Records of HIV-1+ individuals attending Chelsea and Westminster Hospital (1988–2010), were analysed. LTNP were defined as: HIV-1+ for >7 years; ART-naïve; no history of opportunistic infection and normal, stable CD4+ T-cell counts. MIXED procedure in SAS using random intercept model identified long-term stable CD4+ T-cell counts. Survival analysis estimated time since diagnosis until disease progression. Subjects exhibiting long-term stable CD4+ T-cell counts with history below the normal range (<450 cells/µl blood) were compared to LTNP whose CD4+ T-cell count always remained normal. Within these two groups subjects with HIV-1 RNA load below limit of detection (BLD) were identified. Of 14,227 patients, 1,204 were diagnosed HIV-1+ over 7 years ago and were ART-naïve. Estimated time until disease progression for the 20% (239) whose CD4+ T-cell counts remained within the normal range, was 6.2 years (IQR: 2.0 to 9.6); significantly longer than 4.0 years (IQR: 1.0 to 7.3) for patients with historical CD4+ T-cell count below normal (Logrank chi-squared = 21.26; p<0.001). Within a subpopulation of 312 asymptomatic patients, 50 exhibited long-term stable CD4+ T-cell counts. Of these, 13 were LTNP, one of whom met HIC criteria. Of the remaining 37 patients with long-term stable low CD4+ T-cell counts, 3 controlled HIV-1 RNA load BLD. Individuals with stable, normal CD4+ T-cell counts progressed less rapidly than those with low CD4+ T-cell counts. Few LTNP and HIC identified in this and other studies, endorse the need for universal definitions to facilitate comparison

Transient Nature of Long-Term Nonprogression and Broad Virus-Specific Proliferative T-Cell Responses with Sustained Thymic Output in HIV-1 Controllers

HIV-1(+) individuals who, without therapy, conserve cellular anti-HIV-1 responses, present with high, stable CD4(+) T-cell numbers, and control viral replication, facilitate analysis of atypical viro-immunopathology. In the absence of universal definition, immune function in such HIV controllers remains an indication of non-progression.CD4 T-cell responses to a number of HIV-1 proteins and peptide pools were assessed by IFN-gamma ELISpot and lymphoproliferative assays in HIV controllers and chronic progressors. Thymic output was assessed by sjTRECs levels. Follow-up of 41 HIV-1(+) individuals originally identified as "Long-term non-progressors" in 1996 according to clinical criteria, and longitudinal analysis of two HIV controllers over 22 years, was also performed. HIV controllers exhibited substantial IFN-gamma producing and proliferative HIV-1-specific CD4 T-cell responses to both recombinant proteins and peptide pools of Tat, Rev, Nef, Gag and Env, demonstrating functional processing and presentation. Conversely, HIV-specific T-cell responses were limited to IFN-gamma production in chronic progressors. Additionally, thymic output was approximately 19 fold higher in HIV controllers than in age-matched chronic progressors. Follow-up of 41 HIV-1(+) patients identified as LTNP in 1996 revealed the transitory characteristics of this status. IFN-gamma production and proliferative T-cell function also declines in 2 HIV controllers over 22 years.Although increased thymic output and anti-HIV-1 T-cell responses are observed in HIV controllers compared to chronic progressors, the nature of nonprogressor/controller status appears to be transitory

Enrichment of HLA Types and Single-Nucleotide Polymorphism Associated With Non-progression in a Strictly Defined Cohort of HIV-1 Controllers

HIV-1 controllers (HIC) are extremely rare patients with the ability to control viral replication, maintain unchanging CD4 T-cell count, and evade disease progression for extensive periods of time, in the absence of antiretroviral therapy. In order to establish the representation of key genetic correlates of atypical disease progression within a cohort of HIV-1+ individuals who control viral replication, we examine four-digit resolution HLA type and single-nucleotide polymorphisms (SNP) previously identified to be correlated to non-progressive infection, in strictly defined HIC. Clinical histories were examined to identify patients exhibiting HIC status. Genomic DNA was extracted, and high definition HLA typing and genome-wide SNP analysis was performed. Data were compared with frequencies of SNP in European long-term non-progressors (LTNP) and primary infection cohorts. HLA-B alleles associated with atypical disease progression were at very high frequencies in the group of five HIC studied. All four HIC of European ancestry were HLA-B*57+ and half were also HLA-B*27+. All HIC, including one of self-reported African ethnicity, had the HLA-Cw*0602 allele, and the HLA-DQ9 allele was present only in HIC of European ancestry. A median 95% of the top 19 SNP known to be associated with LTNP status was observed in European HIC (range 78–100%); 17/19 of the SNP considered mapped to chromosome 6 in the HLA region, whereas 2/19 mapped to chromosome 8. The HIC investigated here demonstrated high enrichment of HLA types and SNP previously associated with long-term non-progression. These findings suggest that the extreme non-progressive phenotype considered here is associated with a genetic signature characterized by a single-genetic unit centered around the HLA-B*57 haplotype and the possible additive effect of HLA-B*27

Flow chart detailing the identification of LTNP and patients with long-term stable low CD4⁺ T-cell counts from the Chelsea and Westminster HIV Cohort, during the study period 1988–2010.

<p>Flow chart detailing the identification of LTNP and patients with long-term stable low CD4⁺ T-cell counts from the Chelsea and Westminster HIV Cohort, during the study period 1988–2010.</p

Synonyms used to describe HIV-1⁺ patients exhibiting atypical disease progression.

<p>No internationally recognised consensus for terminology currently exists, making comparison between studies difficult. ¹<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029844#pone.0029844-Klein1" target="_blank">[21]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029844#pone.0029844-Cao1" target="_blank">[22]</a>, ²<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029844#pone.0029844-Westrop1" target="_blank">[5]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029844#pone.0029844-Deeks1" target="_blank">[6]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029844#pone.0029844-Grabar1" target="_blank">[19]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029844#pone.0029844-Lambotte1" target="_blank">[23]</a>, ³<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029844#pone.0029844-Walker1" target="_blank">[24]</a>, ⁴<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029844#pone.0029844-Deeks1" target="_blank">[6]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029844#pone.0029844-Migueles1" target="_blank">[18]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029844#pone.0029844-Grabar1" target="_blank">[19]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029844#pone.0029844-Walker1" target="_blank">[24]</a>, ⁵<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029844#pone.0029844-Deeks1" target="_blank">[6]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029844#pone.0029844-Han1" target="_blank">[25]</a>, ⁶<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029844#pone.0029844-Grabar1" target="_blank">[19]</a>, ⁷<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029844#pone.0029844-Westrop1" target="_blank">[5]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029844#pone.0029844-Deeks1" target="_blank">[6]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029844#pone.0029844-Lefrre1" target="_blank">[16]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029844#pone.0029844-Migueles1" target="_blank">[18]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029844#pone.0029844-Grabar1" target="_blank">[19]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029844#pone.0029844-Lambotte1" target="_blank">[23]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029844#pone.0029844-Aiuti1" target="_blank">[26]</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029844#pone.0029844-Migueles3" target="_blank">[28]</a>, ⁸<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029844#pone.0029844-Lefrre1" target="_blank">[16]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029844#pone.0029844-Migueles2" target="_blank">[27]</a>.</p

Time since HIV-1⁺ diagnosis until disease progression in patients who have been infected with HIV-1 for more than 7 years and who remain symptomless in the absence of ART.

<p>Patients are stratified according to a history of at least one CD4⁺ T-cell count below the normal range (<450 cells/µl blood).</p>†, ‡<p>See <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029844#pone-0029844-g001" target="_blank">Figure 1</a> for definition of patient groups.</p>#<p>median (IQR) years.</p><p>p-values using the Logrank chi-squared test.</p