scholarly journals Pol-Driven Replicative Capacity Impacts Disease Progression in HIV-1 Subtype C Infection

2018 ◽  
Vol 92 (19) ◽  
Author(s):  
Doty B. A. Ojwach ◽  
Daniel MacMillan ◽  
Tarylee Reddy ◽  
Vladimir Novitsky ◽  
Zabrina L. Brumme ◽  
...  
Keyword(s):  
Viral Load ◽  
T Cell ◽  
Disease Progression ◽  
Chronic Infection ◽  
Hiv Disease ◽  
Subtype C ◽  
Recombinant Viruses ◽  
Immune Mediated ◽  
Hiv 1

ABSTRACT CD8+ T cell-mediated escape mutations in Gag can reduce HIV-1 replication capacity (RC) and alter disease progression, but less is known about immune-mediated attenuation in other HIV-1 proteins. We generated 487 recombinant viruses encoding RT-integrase from individuals with chronic (n = 406) and recent (n = 81) HIV-1 subtype C infection and measured their in vitro RC using a green fluorescent protein (GFP) reporter T cell assay. In recently infected individuals, reverse transcriptase (RT)-integrase-driven RC correlated significantly with viral load set point (r = 0.25; P = 0.03) and CD4+ T cell decline (P = 0.013). Moreover, significant associations between RT integrase-driven RC and viral load (r = 0.28; P < 0.0001) and CD4+ T cell count (r = −0.29; P < 0.0001) remained in chronic infection. In early HIV infection, host expression of the protective HLA-B*81 allele was associated with lower RC (P = 0.05), as was expression of HLA-B*07 (P = 0.02), suggesting early immune-driven attenuation of RT-integrase by these alleles. In chronic infection, HLA-A*30:09 (in linkage disequilibrium with HLA-B*81) was significantly associated with lower RC (P = 0.05), and all 6 HLA-B alleles with the lowest RC measurements represented protective alleles, consistent with long-term effects of host immune pressures on lowering RT-integrase RC. The polymorphisms V241I, I257V, P272K, and E297K in reverse transcriptase and I201V in integrase, all relatively uncommon polymorphisms occurring in or adjacent to optimally described HLA-restricted cytotoxic T-lymphocyte epitopes, were associated with reduced RC. Together, our data suggest that RT-integrase-driven RC is clinically relevant and provide evidence that immune-driven selection of mutations in RT-integrase can compromise RC. IMPORTANCE Identification of viral mutations that compromise HIV's ability to replicate may aid rational vaccine design. However, while certain escape mutations in Gag have been shown to reduce HIV replication and influence clinical progression, less is known about the consequences of mutations that naturally arise in other HIV proteins. Pol is a highly conserved protein, but the impact of Pol function on HIV disease progression is not well defined. Here, we generated recombinant viruses using the RT-integrase region of Pol derived from HIV-1C-infected individuals with recent and chronic infection and measured their ability to replicate in vitro. We demonstrate that RT-integrase-driven replication ability significantly impacts HIV disease progression. We further show evidence of immune-mediated attenuation in RT-integrase and identify specific polymorphisms in RT-integrase that significantly decrease HIV-1 replication ability, suggesting which Pol epitopes could be explored in vaccine development.

scholarly journals Viral Load and CD4+ T-Cell Dynamics in Primary HIV-1 Subtype C Infection

2009 ◽  
Vol 50 (1) ◽  
pp. 65-76 ◽  
Author(s):  
Vladimir Novitsky ◽  
Elias Woldegabriel ◽  
Lemme Kebaabetswe ◽  
Raabya Rossenkhan ◽  
Busisiwe Mlotshwa ◽  
...  
Keyword(s):  
Viral Load ◽  
T Cell ◽  
Cd4 T Cell ◽  
Subtype C ◽  
Cell Dynamics ◽  
Hiv 1

scholarly journals Hierarchical Targeting of Subtype C Human Immunodeficiency Virus Type 1 Proteins by CD8+ T Cells: Correlation with Viral Load

2004 ◽  
Vol 78 (7) ◽  
pp. 3233-3243 ◽  
Author(s):  
Agatha Masemola ◽  
Tumelo Mashishi ◽  
Greg Khoury ◽  
Phineas Mohube ◽  
Pauline Mokgotho ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Load ◽  
T Cell ◽  
T Cell Responses ◽  
Subtype C ◽  
Viral Control ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT An understanding of the relationship between the breadth and magnitude of T-cell epitope responses and viral loads is important for the design of effective vaccines. For this study, we screened a cohort of 46 subtype C human immunodeficiency virus type 1 (HIV-1)-infected individuals for T-cell responses against a panel of peptides corresponding to the complete subtype C genome. We used a gamma interferon ELISPOT assay to explore the hypothesis that patterns of T-cell responses across the expressed HIV-1 genome correlate with viral control. The estimated median time from seroconversion to response for the cohort was 13 months, and the order of cumulative T-cell responses against HIV proteins was as follows: Nef > Gag > Pol > Env > Vif > Rev > Vpr > Tat > Vpu. Nef was the most intensely targeted protein, with 97.5% of the epitopes being clustered within 119 amino acids, constituting almost one-third of the responses across the expressed genome. The second most targeted region was p24, comprising 17% of the responses. There was no correlation between viral load and the breadth of responses, but there was a weak positive correlation (r = 0.297; P = 0.034) between viral load and the total magnitude of responses, implying that the magnitude of T-cell recognition did not contribute to viral control. When hierarchical patterns of recognition were correlated with the viral load, preferential targeting of Gag was significantly (r = 0.445; P = 0.0025) associated with viral control. These data suggest that preferential targeting of Gag epitopes, rather than the breadth or magnitude of the response across the genome, may be an important marker of immune efficacy. These data have significance for the design of vaccines and for interpretation of vaccine-induced responses.

scholarly journals Magnitude of Functional CD8+ T-Cell Responses to the Gag Protein of Human Immunodeficiency Virus Type 1 Correlates Inversely with Viral Load in Plasma

2002 ◽  
Vol 76 (5) ◽  
pp. 2298-2305 ◽  
Author(s):  
Bradley H. Edwards ◽  
Anju Bansal ◽  
Steffanie Sabbaj ◽  
Janna Bakari ◽  
Mark J. Mulligan ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Load ◽  
T Cell ◽  
Disease Progression ◽  
T Cell Responses ◽  
Cell Responses ◽  
Cell Counts ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The importance of CD8+ T-cell responses in the control of human immunodeficiency virus type 1 (HIV-1) infection has been demonstrated, yet few studies have been able to correlate these responses with markers of HIV-1 disease progression. This study measured cell-mediated immune responses using peripheral blood mononuclear cells (PBMC) obtained from 27 patients with chronic HIV-1 infection, the majority of whom were off antiretroviral therapy. The ELISPOT assay was used to detect gamma interferon-secreting PBMC after stimulation with overlapping HIV-1 peptides spanning the Gag, Pol, Env, and Nef proteins in addition to the baculovirus-derived p24 and gp160 proteins. All volunteers had responses to at least one HIV-1-specific peptide. All but one of the subjects (96%) responded to the Gag peptide pool, and 86% responded to the Pol and/or Nef peptide pools. The magnitude and the breadth of T-cell responses directed to either the Gag or p24 peptide pools correlated inversely with viral load in plasma (r = −0.60, P < 0.001 and r = −0.52, P < 0.005, respectively) and directly with absolute CD4+ T-cell counts (r = 0.54, P < 0.01 and r = 0.39, P < 0.05, respectively) using the Spearman rank correlation test. Responses to the Pol and integrase peptide pools also correlated with absolute CD4+ T-cell counts (r = 0.45, P < 0.05 and r = 0.49, P < 0.01, respectively). No correlation with markers of disease progression was seen with specific T-cell responses directed toward the Env or Nef peptides. These data serve as strong evidence that major histocompatibility complex class I presentation of Gag peptides is an essential feature for any HIV-1 vaccine designed to elicit optimal CD8+ T-cell responses.

scholarly journals Regulatory B cell frequency correlates with markers of HIV disease progression and attenuates anti-HIV CD8+T cell function in vitro

2013 ◽  
Vol 93 (5) ◽  
pp. 811-818 ◽  
Author(s):  
Basile Siewe ◽  
Jack T. Stapleton ◽  
Jeffrey Martinson ◽  
Ali Keshavarzian ◽  
Nazia Kazmi ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Disease Progression ◽  
Cell Function ◽  
Cd8 T Cell ◽  
Hiv Disease ◽  
Cell Frequency ◽  
Regulatory B Cell ◽  
Anti Hiv

scholarly journals Fluidity of HIV-1-Specific T-Cell Responses during Acute and Early Subtype C HIV-1 Infection and Associations with Early Disease Progression

2010 ◽  
Vol 84 (22) ◽  
pp. 12018-12029 ◽  
Author(s):  
Mandla Mlotshwa ◽  
Catherine Riou ◽  
Denis Chopera ◽  
Debra de Assis Rosa ◽  
Roman Ntale ◽  
...  
Keyword(s):  
T Cell ◽  
Disease Progression ◽  
Cell Epitope ◽  
T Cell Responses ◽  
Temporal Patterns ◽  
Viral Escape ◽  
Subtype C ◽  
Cell Responses ◽  
Ifn Γ ◽  
Hiv 1

ABSTRACT Deciphering immune events during early stages of human immunodeficiency virus type 1 (HIV-1) infection is critical for understanding the course of disease. We characterized the hierarchy of HIV-1-specific T-cell gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assay responses during acute subtype C infection in 53 individuals and associated temporal patterns of responses with disease progression in the first 12 months. There was a diverse pattern of T-cell recognition across the proteome, with the recognition of Nef being immunodominant as early as 3 weeks postinfection. Over the first 6 months, we found that there was a 23% chance of an increased response to Nef for every week postinfection (P = 0.0024), followed by a nonsignificant increase to Pol (4.6%) and Gag (3.2%). Responses to Env and regulatory proteins appeared to remain stable. Three temporal patterns of HIV-specific T-cell responses could be distinguished: persistent, lost, or new. The proportion of persistent T-cell responses was significantly lower (P = 0.0037) in individuals defined as rapid progressors than in those progressing slowly and who controlled viremia. Almost 90% of lost T-cell responses were coincidental with autologous viral epitope escape. Regression analysis between the time to fixed viral escape and lost T-cell responses (r = 0.61; P = 0.019) showed a mean delay of 14 weeks after viral escape. Collectively, T-cell epitope recognition is not a static event, and temporal patterns of IFN-γ-based responses exist. This is due partly to viral sequence variation but also to the recognition of invariant viral epitopes that leads to waves of persistent T-cell immunity, which appears to associate with slower disease progression in the first year of infection.

scholarly journals In-vitro Immunomodulatory activity of Azadirachta indica A.Juss. Ethanol: water mixture against HIV associated chronic CD4+ T-cell activation/ exhaustion

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Omalla A. Olwenyi ◽  
Bannet Asingura ◽  
Prossy Naluyima ◽  
Godwin Upoki Anywar ◽  
Justine Nalunga ◽  
...  
Keyword(s):  
Viral Load ◽  
T Cell ◽  
T Cell Activation ◽  
Azadirachta Indica ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Hla Dr ◽  
Hiv 1 ◽  
Hiv Negative

Abstract Background In Sub-Saharan Africa, herbal therapy continues to be utilized for HIV-1 disease management. However, the therapeutic benefits of these substances remain ambiguous. To date, little is known about the effects of these plant extracts on chronic CD4 + T-cell activation and exhaustion which is partly driven by HIV-1 associated microbial translocation. Methods Effects of Azadirachta indica, Momordica foetida and Moringa oleifera ethanol: water mixtures on cell viability were evaluated using the Guava PCA system. Then, an in-vitro cell culture model was developed to mimic CD4+ T cell exposures to antigens following HIV-1 microbial translocation. In this, peripheral blood mononuclear cells (PBMCs) isolated from HIV negative (n = 13), viral load < 1000 copies per mL (n = 10) and viral load > 1000 copies per mL (n = 6) study participants from rural Uganda were treated with Staphylococcus enterotoxin B (SEB). Then, the candidate plant extract (A. indica) was added to test the potential to inhibit corresponding CD4+ T cell activation. Following BD Facs Canto II event acquisition, variations in %CD38, %CD69, Human Leukocyte Antigen -DR (HLA-DR), Programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3), interferon gamma (IFN γ) and interleukin 2 (IL-2) CD4 + T cell expression were evaluated. Results Following exposure to SEB, only A. indica demonstrated a concentration-dependent ability to downregulate the levels of CD4 + T cell activation. At the final concentration of 0.500 μg/mL of A. indica, a significant downregulation of CD4 + CD38 + HLA-DR+ expression was observed in HIV negative (p < 0.0001) and both HIV infected groups (P = 0.0313). This plant extract also significantly lowered SEB induced % CD4+ T cell HLADR, PD-1 and Tim-3 levels. PD-1 and CD69 markers were only significantly downmodulated in only the HIV negative ((p = 0.0001 and p = 0.0078 respectively) and viral load< 1000 copies per ml (p = 0.0078) groups. Conclusion A. indica exhibited the in-vitro immunomodulatory potential to inhibit the continuum of SEB induced CD4+ T-cell activation/ exhaustion without impacting general T-cell specific functions such as cytokine secretion. Additional studies are needed to confirm A. indica as a source of natural products for targeting persistent immune activation and inflammation during ART.

scholarly journals MAVS Genetic Variation Is Associated with Decreased HIV-1 Replication In Vitro and Reduced CD4+ T Cell Infection in HIV-1-Infected Individuals

Viruses ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 764
Author(s):  
Melissa Stunnenberg ◽  
Lisa van Pul ◽  
Joris K. Sprokholt ◽  
Karel A. van Dort ◽  
Sonja I. Gringhuis ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Viral Load ◽  
T Cell ◽  
Viral Replication ◽  
Mononuclear Cells ◽  
Cd4 T Cell ◽  
Lower Percentage ◽  
Cell Counts ◽  
Hiv 1

The mitochondrial antiviral protein MAVS is a key player in the induction of antiviral responses; however, human immunodeficiency virus 1 (HIV-1) is able to suppress these responses. Two linked single nucleotide polymorphisms (SNPs) in the MAVS gene render MAVS insensitive to HIV-1-dependent suppression, and have been shown to be associated with a lower viral load at set point and delayed increase of viral load during disease progression. Here, we studied the underlying mechanisms involved in the control of viral replication in individuals homozygous for this MAVS genotype. We observed that individuals with the MAVS minor genotype had more stable total CD4+ T cell counts during a 7-year follow up and had lower cell-associated proviral DNA loads. Genetic variation in MAVS did not affect immune activation levels; however, a significantly lower percentage of naïve CD4+ but not CD8+ T cells was observed in the MAVS minor genotype. In vitro HIV-1 infection of peripheral blood mononuclear cells (PBMCs) from healthy donors with the MAVS minor genotype resulted in decreased viral replication. Although the precise underlying mechanism remains unclear, our data suggest that the protective effect of the MAVS minor genotype may be exerted by the initiation of local innate responses affecting viral replication and CD4+ T cell susceptibility.

scholarly journals Subtype-Specific Differences in Gag-Protease-Driven Replication Capacity Are Consistent with Intersubtype Differences in HIV-1 Disease Progression

2017 ◽  
Vol 91 (13) ◽  
Author(s):  
Marion W. Kiguoya ◽  
Jaclyn K. Mann ◽  
Denis Chopera ◽  
Kamini Gounder ◽  
Guinevere Q. Lee ◽  
...  
Keyword(s):  
Disease Progression ◽  
Sub Saharan Africa ◽  
Replication Capacity ◽  
Binding Motif ◽  
Replicative Capacity ◽  
Subtype C ◽  
East African ◽  
Recombinant Viruses ◽  
Subtype B ◽  
Hiv 1

ABSTRACT There are marked differences in the spread and prevalence of HIV-1 subtypes worldwide, and differences in clinical progression have been reported. However, the biological reasons underlying these differences are unknown. Gag-protease is essential for HIV-1 replication, and Gag-protease-driven replication capacity has previously been correlated with disease progression. We show that Gag-protease replication capacity correlates significantly with that of whole isolates (r = 0.51; P = 0.04), indicating that Gag-protease is a significant contributor to viral replication capacity. Furthermore, we investigated subtype-specific differences in Gag-protease-driven replication capacity using large well-characterized cohorts in Africa and the Americas. Patient-derived Gag-protease sequences were inserted into an HIV-1 NL4-3 backbone, and the replication capacities of the resulting recombinant viruses were measured in an HIV-1-inducible reporter T cell line by flow cytometry. Recombinant viruses expressing subtype C Gag-proteases exhibited substantially lower replication capacities than those expressing subtype B Gag-proteases (P < 0.0001); this observation remained consistent when representative Gag-protease sequences were engineered into an HIV-1 subtype C backbone. We identified Gag residues 483 and 484, located within the Alix-binding motif involved in virus budding, as major contributors to subtype-specific replicative differences. In East African cohorts, we observed a hierarchy of Gag-protease-driven replication capacities, i.e., subtypes A/C < D < intersubtype recombinants (P < 0.0029), which is consistent with reported intersubtype differences in disease progression. We thus hypothesize that the lower Gag-protease-driven replication capacity of subtypes A and C slows disease progression in individuals infected with these subtypes, which in turn leads to greater opportunity for transmission and thus increased prevalence of these subtypes. IMPORTANCE HIV-1 subtypes are unevenly distributed globally, and there are reported differences in their rates of disease progression and epidemic spread. The biological determinants underlying these differences have not been fully elucidated. Here, we show that HIV-1 Gag-protease-driven replication capacity correlates with the replication capacity of whole virus isolates. We further show that subtype B displays a significantly higher Gag-protease-mediated replication capacity than does subtype C, and we identify a major genetic determinant of these differences. Moreover, in two independent East African cohorts we demonstrate a reproducible hierarchy of Gag-protease-driven replicative capacity, whereby recombinants exhibit the greatest replication, followed by subtype D, followed by subtypes A and C. Our data identify Gag-protease as a major determinant of subtype differences in disease progression among HIV-1 subtypes; furthermore, we propose that the poorer viral replicative capacity of subtypes A and C may paradoxically contribute to their more efficient spread in sub-Saharan Africa.

Young adults HIV-1 infected by vertical transmission in southern Brazil – Clinical, demographic, and virological features

2017 ◽  
Vol 28 (14) ◽  
pp. 1419-1425
Author(s):  
Beatris M Martin ◽  
Jucélia S Santos ◽  
Fernanda V Scapinello ◽  
Clea EL Ribeiro ◽  
Monica M Gomes-da-Silva ◽  
...  
Keyword(s):  
Disease Progression ◽  
Vertical Transmission ◽  
Venous Blood ◽  
Case Series ◽  
Hiv Disease ◽  
Southern Brazil ◽  
Subtype C ◽  
Viral Subtype ◽  
Hiv 1

Combination antiretroviral therapy promotes longer life expectancy, making it possible for perinatally HIV-infected patients to achieve adulthood. Past therapy was not always optimized, suggesting that virological and host features may also play a role in survival. The aim of this study is to describe characteristics of HIV disease progression associated with virological features in adolescents perinatally that were HIV infected. A case series was conducted including 81 patients that were in follow-up at Hospital de Clínicas/Universidade Federal do Paraná, Curitiba, Brazil. Venous blood was collected to conduct tropism and viral subtype assays. The median age was 19 years old (interquartile range 18–21), and a majority of patients were female (54.3%). Viral subtype was obtained for 66 (82%) patients, and subtypes B and C were found in 34% and 59%, respectively. Tropism assay was conducted in 55 (67%) patients: 71% were R5 and 29% X4. Distribution of viral tropism and subtype shows a significant association of subtype C with R5 tropism. Subtype C is more prevalent in southern Brazil and also in the population infected with HIV by vertical transmission. Both R5 tropism and subtype C are associated with slower progression to AIDS. The survival of these patients may be related to virological features present in a benign pattern of disease progression.

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