Once-daily Doravirine in Human Immunodeficiency Virus Type 1–Infected, Antiretroviral-naive Adults: An Integrated Efficacy Analysis

2019 ◽  
Vol 70 (7) ◽  
pp. 1344-1352 ◽  
Author(s):  
Chloe Orkin ◽  
Jean-Michel Molina ◽  
Johan Lombaard ◽  
Edwin DeJesus ◽  
Anthony Rodgers ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Cell Count ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cd4 T Cell ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Cd4 T Cell Count

AbstractBackgroundDoravirine (DOR) demonstrated noninferior efficacy to darunavir plus ritonavir (DRV+r) and efavirenz (EFV) in 2 ongoing phase 3 trials: DRIVE-FORWARD (NCT02275780) and DRIVE-AHEAD (NCT02403674).MethodsThis prespecified analysis pooled efficacy data through the first 48 weeks of DRIVE-FORWARD and DRIVE-AHEAD from the DOR groups (DOR/lamivudine [3TC]/tenofovir disoproxil fumarate [TDF] or DOR [100 mg daily] with emtricitabine [FTC]/TDF or abacavir [ABC]/3TC [n = 747]) compared with DRV+r (800/100 mg daily) with FTC/TDF or ABC/3TC (n = 383) or EFV/FTC/TDF (600/200/300 mg daily; n = 364). Efficacy assessments included the proportion of participants with human immunodeficiency virus type 1 (HIV-1) RNA <50 copies/mL and change in CD4+ T-cell count.ResultsAt week 48, DOR demonstrated noninferior efficacy to DRV+r and EFV, with 84.1% of DOR-treated participants achieving HIV-1 RNA <50 copies/mL compared with 79.9% of the DRV+r and 80.8% of the EFV groups. Results were similar across demographic/prognostic subpopulations, including baseline plasma HIV-1 RNA, gender, race, and HIV-1 subtype. Mean increases from baseline in CD4+ T-cell count through 48 weeks were 195.5 cells/mm3 for DOR, 185.6 cells/mm3 for DRV+r, and 188.4 cells/mm3 for EFV/FTC/TDF.ConclusionsDOR, as a single entity (in combination with other antiretroviral agents) and as a fixed-dose combination (DOR/3TC/TDF), demonstrated noninferior efficacy to DRV+r and EFV as assessed by the proportion of HIV-1-infected, treatment-naive adults with HIV-1 RNA <50 copies/mL.Clinical Trials RegistrationNCT02275780 and NCT02403674.

scholarly journals Entry and Transcription as Key Determinants of Differences in CD4 T-Cell Permissiveness to Human Immunodeficiency Virus Type 1 Infection

2004 ◽  
Vol 78 (19) ◽  
pp. 10747-10754 ◽  
Author(s):  
Angela Ciuffi ◽  
Gabriela Bleiber ◽  
Miguel Muñoz ◽  
Raquel Martinez ◽  
Corinne Loeuillet ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Virus Production ◽  
Cd4 T Cell ◽  
Total Variance ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Isolated primary human cells from different donors vary in their permissiveness—the ability of cells to be infected and sustain the replication of human immunodeficiency virus type 1 (HIV-1). We used replicating HIV-1 and single-cycle lentivirus vectors in a population approach to identify polymorphic steps during viral replication. We found that phytohemagglutinin-stimulated CD4+ CD45RO+ CD57− T cells from healthy blood donors (n = 128) exhibited a 5.2-log-unit range in virus production. For 20 selected donors representing the spectrum of CD4 T-cell permissiveness, we could attribute up to 42% of the total variance in virus production to entry factors and 48% to postentry steps. Efficacy at key intracellular steps of the replicative cycle (reverse transcription, integration, transcription and splicing, translation, and budding and release) varied from 0.71 to 1.45 log units among donors. However, interindividual differences in transcription efficiency alone accounted for 64 to 83% of the total variance in virus production that was attributable to postentry factors. While vesicular stomatitis virus G protein-mediated fusion was more efficacious than CCR5/CD4 entry, the latter resulted in greater transcriptional activity per proviral copy. The phenotype of provirus transcription was stable over time, indicating that it represents a genetic trait.

scholarly journals Mutually Exclusive T-Cell Receptor Induction and Differential Susceptibility to Human Immunodeficiency Virus Type 1 Mutational Escape Associated with a Two-Amino-Acid Difference between HLA Class I Subtypes

2006 ◽  
Vol 81 (4) ◽  
pp. 1619-1631 ◽  
Author(s):  
Xu G. Yu ◽  
Mathias Lichterfeld ◽  
Senica Chetty ◽  
Katie L. Williams ◽  
Stanley K. Mui ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Hla Class I ◽  
Viral Escape ◽  
Class I ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The relative contributions of HLA alleles and T-cell receptors (TCRs) to the prevention of mutational viral escape are unclear. Here, we examined human immunodeficiency virus type 1 (HIV-1)-specific CD8+ T-cell responses restricted by two closely related HLA class I alleles, B*5701 and B*5703, that differ by two amino acids but are both associated with a dominant response to the same HIV-1 Gag epitope KF11 (KAFSPEVIPMF). When this epitope is presented by HLA-B*5701, it induces a TCR repertoire that is highly conserved among individuals, cross-recognizes viral epitope variants, and is rarely associated with mutational escape. In contrast, KF11 presented by HLA-B*5703 induces an entirely different, more heterogeneous TCR β-chain repertoire that fails to recognize specific KF11 escape variants which frequently arise in clade C-infected HLA-B*5703+ individuals. These data show the influence of HLA allele subtypes on TCR selection and indicate that extensive TCR diversity is not a prerequisite to prevention of allowable viral mutations.

scholarly journals Enhanced immunogenicity using an alphavirus replicon DNA vaccine against human immunodeficiency virus type 1

2005 ◽  
Vol 86 (2) ◽  
pp. 349-354 ◽  
Author(s):  
Eva K. L. Nordström ◽  
Mattias N. E. Forsell ◽  
Christina Barnfield ◽  
Eivor Bonin ◽  
Tomas Hanke ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Dna Vaccine ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Semliki Forest Virus ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Hiv 1

With the human immunodeficiency virus type 1 (HIV-1) epidemic expanding at increasing speed, development of a safe and effective vaccine remains a high priority. One of the most central vaccine platforms considered is plasmid DNA. However, high doses of DNA and several immunizations are typically needed to achieve detectable T-cell responses. In this study, a Semliki Forest virus replicon DNA vaccine designed for human clinical trials, DREP.HIVA, encoding an antigen that is currently being used in human trials in the context of a conventional DNA plasmid, pTHr.HIVA, was generated. It was shown that a single immunization of DREP.HIVA stimulated HIV-1-specific T-cell responses in mice, suggesting that the poor immunogenicity of conventional DNA vaccines may be enhanced by using viral replicon-based plasmid systems. The results presented here support the evaluation of Semliki Forest virus replicon DNA vaccines in non-human primates and in clinical studies.

scholarly journals Ontogeny and Specificities of Mucosal and Blood Human Immunodeficiency Virus Type 1-Specific CD8+ Cytotoxic T Lymphocytes

2003 ◽  
Vol 77 (1) ◽  
pp. 291-300 ◽  
Author(s):  
L. Musey ◽  
Y. Ding ◽  
J. Cao ◽  
J. Lee ◽  
C. Galloway ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cytotoxic T Lymphocyte ◽  
Infected Individual ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Induction of adaptive immunity to human immunodeficiency virus type 1 (HIV-1) at the mucosal site of transmission is poorly understood but crucial in devising strategies to control and prevent infection. To gain further understanding of HIV-1-specific T-cell mucosal immunity, we established HIV-1-specific CD8+ cytotoxic T-lymphocyte (CTL) cell lines and clones from the blood, cervix, rectum, and semen of 12 HIV-1-infected individuals and compared their specificities, cytolytic function, and T-cell receptor (TCR) clonotypes. Blood and mucosal CD8+ CTL had common HIV-1 epitope specificities and major histocompatibility complex restriction patterns. Moreover, both systemic and mucosal CTL lysed targets with similar efficiency, primarily through the perforin-dependent pathway in in vitro studies. Sequence analysis of the TCRβ VDJ region revealed in some cases identical HIV-1-specific CTL clones in different compartments in the same HIV-1-infected individual. These results clearly establish that a subset of blood and mucosal HIV-1-specific CTL can have a common origin and can traffic between anatomically distinct compartments. Thus, these effectors can provide immune surveillance at the mucosa, where rapid responses are needed to contain HIV-1 infection.

scholarly journals Purifying selection of CCR5-tropic human immunodeficiency virus type 1 variants in AIDS subjects that have developed syncytium-inducing, CXCR4-tropic viruses

2006 ◽  
Vol 87 (5) ◽  
pp. 1285-1294 ◽  
Author(s):  
Guerau Fernàndez ◽  
Anuska Llano ◽  
Miriam Esgleas ◽  
Bonaventura Clotet ◽  
José A. Esté ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Purifying Selection ◽  
Selective Pressures ◽  
Cell Counts ◽  
Immunodeficiency Virus ◽  
Hiv 1

Human immunodeficiency virus type 1 (HIV-1) infection is established by virus variants that use the CCR5 co-receptor for entry (CCR5-tropic or R5 variants), whereas viruses that use CXCR4 as co-receptor (CXCR4-tropic or X4 variants) emerge during disease progression in approximately 50 % of infected subjects. X4 variants may have a higher fitness ex vivo and their detection is usually accompanied by faster T-cell depletion and the onset of AIDS in HIV-1-positive individuals. Here, the relationship between the sequence variation of the HIV-1 env V3–V5 region and positive selective pressure on R5 and X4 variants from infected subjects with CD4 T cell counts below 200 cells μl−1 was studied. A correlation was found between genetic distance and CD4+ cell count at late stages of the disease. R5 variants that co-existed with X4 variants were significantly less heterogeneous than R5 variants from subjects without X4 variants (P<0·0001). Similarly, X4 variants had a significantly higher diversity than R5 variants (P<0·0001), although residues under positive selection had a similar distribution pattern in both variants. Therefore, both X4 and R5 variants were subjected to high selective pressures from the host. Furthermore, the interaction between X4 and R5 variants within the same subject resulted in a purifying selection on R5 variants, which only survived as a homogeneous virus population. These results indicate that R5 variants from X4 phenotype samples were highly homogeneous and under weakly positive selective pressures. In contrast, R5 variants from R5 phenotype samples were highly heterogeneous and subject to positive selective pressures.

scholarly journals Human immunodeficiency virus type 1-infected individuals make autoantibodies that bind to CD43 on normal thymic lymphocytes.

1990 ◽  
Vol 172 (4) ◽  
pp. 1151-1158 ◽  
Author(s):  
B Ardman ◽  
M A Sikorski ◽  
M Settles ◽  
D E Staunton
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
T Lymphocytes ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Lupus Erythematosus ◽  
Viral Infections ◽  
Immunodeficiency Virus ◽  
Hiv 1

Sera from human immunodeficiency virus type 1 (HIV-1)-infected and -noninfected individuals were screened for antibodies that could bind to native T cell differentiation antigens. Antibodies that could immunoprecipitate CD43 (sialophorin, leukosialin) from a T cell lymphoma line were detected in sera from 27% of patients, and antibodies that could bind specifically to transfected cells expressing CD43 were detected in 47% of patients. The anti-CD43 antibodies were related to HIV-1 infection in that no patients with other chronic viral infections or systemic lupus erythematosus contained such antibodies in their sera. The anti-CD43 autoantibodies bound to a partially sialylated form of CD43 expressed by normal human thymocytes, but not by normal, circulating T lymphocytes. However, the determinant(s) recognized by the anti-CD43 autoantibodies was present on a large proportion of circulating T lymphocytes, but masked from antibody recognition by sialic acid residues. These results demonstrate that HIV-1 infection is specifically associated with the production of autoantibodies that bind to a native T cell surface antigen.

scholarly journals Sequential Turnover of Human Immunodeficiency Virus Type 1 env throughout the Course of Infection

2006 ◽  
Vol 80 (21) ◽  
pp. 10591-10599 ◽  
Author(s):  
Tara M. Riddle ◽  
Norah J. Shire ◽  
Marc S. Sherman ◽  
Kelly F. Franco ◽  
Haynes W. Sheppard ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Cell Loss ◽  
Cd4 Counts ◽  
Immunodeficiency Virus ◽  
Hiv 1 ◽  
Over Time

ABSTRACT We examined the rates of variant population turnover of the V1-V2 and V4-V5 hypervariable domains of the human immunodeficiency virus type 1 (HIV-1) gp120 molecule in longitudinal plasma samples from 14 men with chronic HIV-1 infection using heteroduplex tracking assays (HTA). Six men had high rates of CD4+ T-cell loss, and eight men had low rates of CD4+ T-cell loss over 2.5 to 8 years of infection. We found that V1-V2 and V4-V5 env populations changed dramatically over time in all 14 subjects; the changes in these regions were significantly correlated with each another over time. The subjects with rapid CD4 loss had significantly less change in their env populations than the subjects with slow CD4 loss. The two subjects with rapid CD4 loss and sustained low CD4 counts (<150/μl for at least 2 years) showed stabilization of their V1-V2 and V4-V5 populations as reflected by low levels of total change in HTA pattern and low HTA indices (a novel measure of the emergence of new bands and band distribution); this stabilization was not observed in other subjects. The stabilization of env variant populations at low CD4 counts following periods of rapid viral evolution suggests that selective pressure on env, likely from new immune responses, is minimal when CD4 counts drop dramatically and remain low for extended periods of time.

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