A Novel Sample Selection Approach to Aid the Identification of Factors That Correlate With the Control of HIV-1 Infection

Individuals infected with HIV display varying rates of viral control and disease progression, with a small percentage of individuals being able to spontaneously control infection in the absence of treatment. In attempting to define the correlates associated with natural protection against HIV, extreme heterogeneity in the datasets generated from systems methodologies can be further complicated by the inherent variability encountered at the population, individual, cellular and molecular levels. Furthermore, such studies have been limited by the paucity of well-characterised samples and linked epidemiological data, including duration of infection and clinical outcomes. To address this, we selected 10 volunteers who rapidly and persistently controlled HIV, and 10 volunteers each, from two control groups who failed to control (based on set point viral loads) from an acute and early HIV prospective cohort from East and Southern Africa. A propensity score matching approach was applied to control for the influence of five factors (age, risk group, virus subtype, gender, and country) known to influence disease progression on causal observations. Fifty-two plasma proteins were assessed at two timepoints in the 1st year of infection. We independently confirmed factors known to influence disease progression such as the B*57 HLA Class I allele, and infecting virus Subtype. We demonstrated associations between circulating levels of MIP-1α and IL-17C, and the ability to control infection. IL-17C has not been described previously within the context of HIV control, making it an interesting target for future studies to understand HIV infection and transmission. An in-depth systems analysis is now underway to fully characterise host, viral and immunological factors contributing to control.

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Control of the HIV-1 Load Varies by Viral Subtype in a Large Cohort of African Adults With Incident HIV-1 Infection

The Journal of Infectious Diseases ◽

10.1093/infdis/jiz127 ◽

2019 ◽

Vol 220 (3) ◽

pp. 432-441 ◽

Cited By ~ 3

Author(s):

Matt A Price ◽

Wasima Rida ◽

William Kilembe ◽

Etienne Karita ◽

Mubiana Inambao ◽

...

Keyword(s):

Hla Class I ◽

Subtype C ◽

Viral Control ◽

Viral Loads ◽

Viral Subtype ◽

Immunodeficiency Virus ◽

Time Of Infection ◽

Subtype A ◽

Hiv 1

Abstract Few human immunodeficiency virus (HIV)–infected persons can maintain low viral levels without therapeutic intervention. We evaluate predictors of spontaneous control of the viral load (hereafter, “viral control”) in a prospective cohort of African adults shortly after HIV infection. Viral control was defined as ≥2 consecutively measured viral loads (VLs) of ≤10 000 copies/mL after the estimated date of infection, followed by at least 4 subsequent measurements for which the VL in at least 75% was ≤10 000 copies/mL in the absence of ART. Multivariable logistic regression characterized predictors of viral control. Of 590 eligible volunteers, 107 (18.1%) experienced viral control, of whom 25 (4.2%) maintained a VL of 51–2000 copies/mL, and 5 (0.8%) sustained a VL of ≤50 copies/mL. The median ART-free follow-up time was 3.3 years (range, 0.3–9.7 years). Factors independently associated with control were HIV-1 subtype A (reference, subtype C; adjusted odds ratio [aOR], 2.1 [95% confidence interval {CI}, 1.3–3.5]), female sex (reference, male sex; aOR, 1.8 [95% CI, 1.1–2.8]), and having HLA class I variant allele B*57 (reference, not having this allele; aOR, 1.9 [95% CI, 1.0–3.6]) in a multivariable model that also controlled for age at the time of infection and baseline CD4+ T-cell count. We observed strong associations between infecting HIV-1 subtype, HLA type, and sex on viral control in this cohort. HIV-1 subtype is important to consider when testing and designing new therapeutic and prevention technologies, including vaccines.

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Tumor Necrosis Factor α Is Associated With Viral Control and Early Disease Progression in Patients With HIV Type 1 Infection

The Journal of Infectious Diseases ◽

10.1093/infdis/jiu206 ◽

2014 ◽

Vol 210 (7) ◽

pp. 1042-1046 ◽

Cited By ~ 21

Author(s):

Sagar A. Vaidya ◽

Christian Korner ◽

Michael N. Sirignano ◽

Molly Amero ◽

Sue Bazner ◽

...

Keyword(s):

Tumor Necrosis Factor ◽

Disease Progression ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Early Disease ◽

Viral Control ◽

Hiv Type 1 ◽

Factor Α ◽

Necrosis Factor

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The characteristics of the HIV-1 Env glycoprotein contribute to viral pathogenesis

10.1101/2021.07.07.451566 ◽

2021 ◽

Author(s):

Silvia Perez-Yanes ◽

Maria Pernas ◽

Silvia Marfil ◽

Romina Cabrera-Rodríguez ◽

Raquel Ortiz ◽

...

Keyword(s):

Functional Characteristic ◽

Elite Controllers ◽

Clinical Progression ◽

Viral Control ◽

Clinical Phenotypes ◽

Viral Loads ◽

Variable Contribution ◽

Gp120 Subunit ◽

Hiv 1

The understanding of HIV-1 pathogenesis and clinical progression is incomplete because of the variable contribution of host, immune and viral factors. The involvement of viral factors has been investigated in extreme clinical phenotypes from rapid progressors to long-term non-progressors (LTNPs). Among HIV-1 proteins, the envelope glycoprotein complex (Env) has concentrated many studies for its important role in the immune response and in the first steps of viral replication. In this study, we analyzed the contribution of 41 Envs from 24 patients with different clinical progression rates and viral loads (VLs), LTNP-Elite Controllers (LTNP-ECs); Viremic LTNPs (vLTNPs), and non-controller’s individuals contemporary to LTNPs or recent, named Old and Modern progressors. We analyzed the Env expression, the fusion and cell-to-cell transfer capacities as well as viral infectivity. The sequence and phylogenetic analysis of Envs were also performed. In every functional characteristic, the Envs from subjects with viral control (LTNP-ECs and vLTNPs) showed significant lower performance compared to those from the progressor individuals (Old and Modern). Regarding sequence analysis, the variable loops of the gp120 subunit of the Env (i.e., V2, V4 and mainly V5) of the progressor individuals showed longer and more glycosylated sequences than controller subjects. Therefore, HIV-1 Envs presenting poor viral functions and shorter sequences were associated with viremic control and the non-progressor clinical phenotype, whereas functional Envs were associated with the lack of virological control and progressor clinical phenotypes. These correlations support the central role of Env genotypic and phenotypic characteristics in the in vivo HIV-1 infection and pathogenesis.

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The First Complete Genome Sequences of Hepatitis C Virus Subtype 2b from Latin America: Molecular Characterization and Phylogeographic Analysis

Proceedings ◽

10.3390/proceedings2020050121 ◽

2020 ◽

Vol 50 (1) ◽

pp. 121

Author(s):

Natália Spitz ◽

José J. Barros ◽

Kycia M. do Ó ◽

Carlos E. Brandão-Mello ◽

Natalia M. Araujo

Keyword(s):

Latin America ◽

Hepatitis C Virus ◽

Hepatitis C ◽

Latin American ◽

Complete Genome ◽

Direct Sequencing ◽

Epidemiological Data ◽

National Prevalence ◽

Latin American Countries ◽

Virus Subtype

The hepatitis C virus (HCV) has remarkable genetic diversity and exists as eight genotypes (1 to 8) with distinct geographic distributions. No complete genome sequence of HCV subtype 2b (HCV-2b) is available from Latin American countries, and the factors underlying its emergence and spread within the continent remain unknown. The present study was conducted to determine the first full-length genomic sequences of HCV-2b isolates from Latin America and reconstruct the spatial and temporal diversification of this subtype in Brazil. Nearly complete HCV-2b genomes isolated from two Brazilian patients were obtained by direct sequencing of long PCR fragments and analyzed together with reference sequences using the Bayesian coalescent and phylogeographic framework approaches. The two HCV-2b genomes were 9318 nucleotides (nt) in length (nt 37–9354). Interestingly, the long RT-PCR technique was able to detect the co-circulation of viral variants that contained an in-frame deletion of 2022 nt, encompassing E1, E2, and p7 proteins. Spatiotemporal reconstruction analyses suggest that HCV-2b had a single introduction in Brazil during the early 1980s, displaying an epidemic history characterized by a low and virtually constant population size to date. These results coincide with epidemiological data in Brazil and may explain the low national prevalence of this subtype.

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A17 The effect of intra-host evolution of HIV-2 capsid on disease progression

Virus Evolution ◽

10.1093/ve/vez002.016 ◽

2019 ◽

Vol 5 (Supplement_1) ◽

Author(s):

M T Boswell ◽

A Palm ◽

S Karlson ◽

F Månsson ◽

H Norrgren ◽

...

Keyword(s):

West Africa ◽

Disease Progression ◽

Conformational Changes ◽

Horizontal Transmission ◽

Evolutionary Rates ◽

Survival Times ◽

Infected People ◽

Viral Loads ◽

Hiv 1

Abstract The human immunodeficiency virus type 2 (HIV-2) is an important cause of acquired immune deficiency syndrome (AIDS) in West Africa. The virus started circulating in humans around 1938 and has spread predominantly within West Africa with an estimated 1–2 million people being infected today. Compared with the pandemic HIV-1, HIV-2 infected people have longer AIDS-free survival times, higher CD4+ counts and lower risk of vertical and horizontal transmission. Approximately 35 per cent of HIV-2 infected individuals are classified as so-called long-term non-progressors with undetectable viral loads and limited disease progression after 10 years of follow-up. It has been shown that HIV-2 is more sensitive to the host restriction factor TRIM5α when compared with HIV-1, and this has been linked to conformational changes in the retroviral capsid. TRIM5α binds at the interface between three capsid hexamers, initiates early uncoating and proteasomal degradation. TRIM5 genotype has shown only modest effects on HIV-1 disease outcomes. HIV-2 capsid sequences bearing a specific poly-proline motif have been associated with lower viral loads and presentation of protective HLA I-restricted epitopes. The major aims of this study were to (1) determine HIV-2 capsid intra-host evolutionary rates and (2) identify residues that are affected by positive selection and that can be linked to HIV-2 viral load and disease progression in conjunction with TRIM5 genotype. The Guinea-Bissau Police cohort is unique, with decades of relatively frequent follow-up. One hundred and sixty-five patients were included for genotyping of TRIM5, 62 females and 103 males. Median age at enrolment was 52.6 years (range 30–87) and 7.9 per cent of patients had a CD4 percentage < 15 per cent at enrolment. Six of these individuals were included for amplification of HIV-2 capsid from longitudinally collected samples. Viral RNA was extracted from stored blood plasma samples and capsid of the circulating viral quasispecies was amplified, cloned, and sequenced, as previously described. Bayesian analysis will be used to determine intra-host evolutionary rates, dN/dS ratios and how these parameters associate with disease progression and TRIM5 genotype.

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HLA Class I Homozygosity Accelerates Disease Progression in Human Immunodeficiency Virus Type 1 Infection

AIDS Research and Human Retroviruses ◽

10.1089/088922299311277 ◽

1999 ◽

Vol 15 (4) ◽

pp. 317-324 ◽

Cited By ~ 122

Author(s):

Jianming Tang ◽

Caroline Costello ◽

Ireneus P.M. Keet ◽

Charles Rivers ◽

Susan Leblanc ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Disease Progression ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Hla Class I ◽

Class I ◽

Immunodeficiency Virus

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Photopheresis in HIV-1 Infected Patients (pt) using Benzoporphyrin Derivative (BPD-MA) Induces Apoptosis in CD4 Cells, Increases Intracellular Expression of Chemokines and Decreases HIV Infectivity and Viral Load.

Blood ◽

10.1182/blood.v104.11.3836.3836 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3836-3836

Author(s):

Zale P. Bernstein ◽

Thomas Dougherty ◽

Stanley A. Schwartz ◽

Sandra Gollnick ◽

Carleton Stewart ◽

...

Keyword(s):

Viral Load ◽

Immune System ◽

Ex Vivo ◽

Light Exposure ◽

Area Under The Curve ◽

Additional Patient ◽

Viral Control ◽

Viral Loads ◽

Hiv 1

Abstract HIV is able to elude both cellular and humoral arms of the immune system; thereby making viral control difficult. Extra corporeal photochemotherapy (ECP) or photopheresis is an immunomodulatory therapy in which lymphocytes are reinfused into the host after exposure to a photoactive compound and ultraviolet A light. It is an effective therapeutic approach to several disorders of the immune system including acute and chronic graft-versus-host disease, scleroderma, and cutaneous T-cell lymphoma. This process may offer a novel approach to viral control with minimal or no toxicity. We initiated an ex vivo and subsequently a clinical pilot trial utilizing Benzoporphyrin Derivative as the photosensitive compound. Ex vivo dosing studies identified the minimum energy levels of light exposure and concentrations of BPD that eradicated both cell-free and cell-associated HIV-1 infectivity without destroying the virus particles or infected leukocytes. Leukocytes so treated remained viable. They did demonstrate altered cytokine and chemokine expression with apoptosis induced in a minority of CD4 but not CD8 positive cells. A pilot in vivo, 24 week clinical trial in seven HIV-1 infected patients (all were required, upon entry, to have viral loads of > 10,000) using the photopheresis parameters established above demonstrated that the treatment was well tolerated and beneficial. Three individuals who had rapidly rising viral loads prior to initiating therapy stabilized once treatment began. Two of which had a (sustained) greater than.5 log decrement and 5 had stable plasma viral loads (less than a.5 log increment or decrement) with varied effects on absolute CD4 and CD8 positive lymphocytes counts. One subject achieved a greater than 1 log decrement in HIV-1 plasma viral load also developed undetectable in vivo cell-free and cell-associated HIV-1 infectivity while demonstrating an increased in vitro lymphocyte mitogen stimulation index. Subsequently, under amended protocol 3 additional 12 month courses were administered to one additional patient and two of the previous enrollees. The area under the curve for viral load (viral load x # of weeks) for these ten courses of therapy showed a significant decrease from pre to post therapy (p 0.007). There were no significant changes in CD4 or CD8 numbers area under the curve (CD4 number # of weeks and CD8 number x # of weeks). None of the subjects developed an AIDS defining illness during the course of therapy nor were there any treatment associated toxicities. These studies suggest that ECP augments activity of various arms of the immune system without any significant toxicity and may be effective in controlling HIV replication. We have now instituted a Phase II study utilizing long-term photopheresis (twice monthly for 48 weeks) to further determine efficacy and mechanism of activity.

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Photopheresis in HIV-1 Infected Patients (Pt) Using Benzoporphyrin Derivative (BPD-MA) Induces Apoptosis in CD4 Cells, Increases Cytolytic T-Cell Activity, Intracellular Expression of Chemokines, and Decreases HIV Infectivity and Viral Load.

Blood ◽

10.1182/blood.v108.11.1257.1257 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1257-1257

Author(s):

Zale P. Bernstein ◽

Thomas Dougherty ◽

Stanley Schwartz ◽

Sandra Gollnick ◽

Carleton Stewart ◽

...

Keyword(s):

Viral Load ◽

Immune System ◽

T Cell ◽

Ex Vivo ◽

Cell Activity ◽

Area Under The Curve ◽

Viral Control ◽

Viral Loads ◽

Hiv 1

Abstract HIV is able to elude both cellular and humoral arms of the immune system; thereby making viral control difficult. Extra corporeal photochemotherapy (ECP) or photopheresis is an immunomodulatory therapy in which lymphocytes are reinfused into the host after exposure to a photoactive compound and ultraviolet A light. It is an effective therapeutic approach to several disorders of the immune system including acute and chronic graft-versus-host disease, scleroderma, and cutaneous T-cell lymphoma. This process may offer a novel approach to viral control with minimal or no toxicity. We initiated an ex vivo and subsequently a clinical pilot trial utilizing Benzoporphyrin Derivative as the photosensitive compound. Ex vivo dosing studies identified the minimum energy levels of light exposure and concentrations of BPD that eradicated both cell-free and cell-associated HIV-1 infectivity without destroying the virus particles or infected leukocytes. Leukocytes so treated remained viable. They did demonstrate altered cytokine and chemokine expression with apoptosis induced in a minority of CD4 but not CD8 positive cells. Furthermore, there was a statistically significant increase in cytolytic T-cell activity expressed as percentage of granzyme-B release. A pilot in vivo, 24 week clinical trial in seven HIV-1 infected patients (all were required, upon entry, to have viral loads of > 10,000) using the photopheresis parameters established above demonstrated that the treatment was well tolerated and beneficial. Three individuals who had rapidly rising viral loads prior to initiating therapy stabilized once treatment began. Two of which had a (sustained) greater than .5 log decrement and 5 had stable plasma viral loads (less than a .5 log increment or decrement) with varied effects on absolute CD4 and CD8 positive lymphocytes counts. One subject achieved a greater than 1 log decrement in HIV-1 plasma viral load also developed undetectable in vivo cell-free and cell-associated HIV-1 infectivity while demonstrating an increased in vitro lymphocyte mitogen stimulation index. Subsequently, under amended and successor protocol 5 additional 12 month courses were administered to three additional patients and two of the previous enrollees. The area under the curve for viral load (viral load x # of weeks) for these twelve courses of therapy showed a significant decrease from pre to post therapy (p 0.007). There were no significant changes in CD4 or CD8 numbers area under the curve (CD4 number # of weeks and CD8 number x # of weeks). None of the subjects developed an AIDS defining illness during the course of therapy nor were there any treatment associated toxicities. These studies suggest that ECP augments activity of various arms of the immune system without any significant toxicity and may be effective in controlling HIV replication. We now plan a randomized Phase II study utilizing long-term photopheresis (twice monthly for 48 weeks) in addition to anti-retroviral therapy versus anti-retroviral therapy alone to further determine efficacy and mechanism of activity.

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Effective T-Cell Responses Select Human Immunodeficiency Virus Mutants and Slow Disease Progression

Journal of Virology ◽

10.1128/jvi.00022-07 ◽

2007 ◽

Vol 81 (12) ◽

pp. 6742-6751 ◽

Cited By ~ 85

Author(s):

A. J. Frater ◽

H. Brown ◽

A. Oxenius ◽

H. F. Günthard ◽

B. Hirschel ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Disease Progression ◽

T Cell Responses ◽

Hla Class I ◽

Class I ◽

Cell Responses ◽

Hla Class I Molecules ◽

Immunodeficiency Virus ◽

African Patients

ABSTRACT The possession of some HLA class I molecules is associated with delayed progression to AIDS. The mechanism behind this beneficial effect is unclear. We tested the idea that cytotoxic T-cell responses restricted by advantageous HLA class I molecules impose stronger selection pressures than those restricted by other HLA class I alleles. As a measure of the selection pressure imposed by HLA class I alleles, we determined the extent of HLA class I-associated epitope variation in a cohort of European human immunodeficiency virus (HIV)-positive individuals (n = 84). We validated our findings in a second, distinct cohort of African patients (n = 516). We found that key HIV epitopes restricted by advantageous HLA molecules (B27, B57, and B51 in European patients and B5703, B5801, and B8101 in African patients) were more frequently mutated in individuals bearing the restricting HLA than in those who lacked the restricting HLA class I molecule. HLA alleles associated with clinical benefit restricted certain epitopes for which the consensus peptides were frequently recognized by the immune response despite the circulating virus's being highly polymorphic. We found a significant inverse correlation between the HLA-associated hazard of disease progression and the mean HLA-associated prevalence of mutations within epitopes (P = 0.028; R 2 = 0.34). We conclude that beneficial HLA class I alleles impose strong selection at key epitopes. This is revealed by the frequent association between effective T-cell responses and circulating viral escape mutants and the rarity of these variants in patients who lack these favorable HLA class I molecules, suggesting a significant pressure to revert.

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