Lowered Rilpivirine Exposure During the Third Trimester of Pregnancy in Human Immunodeficiency Virus Type 1–Infected Women

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) entry is an attractive target for therapeutic intervention. Two drugs that inhibit this process have been approved: the fusion inhibitor T20 (enfuvirtide [Fuzeon]) and, more recently, the CCR5 blocker maraviroc (Selzentry). T1249 is a second-generation fusion inhibitor with improved antiviral potency compared to the first-generation peptide T20. We selected T1249-resistant HIV-1 variants in vitro by serial virus passage in the presence of increasing T1249 doses after passage with wild-type and T20-resistant variants. Sequence analysis revealed the acquisition of substitutions within the HR1 region of the gp41 ectodomain. The virus acquired mutations of residue V38 to either E or R in 10 of 19 cultures. Both E and R at position 38 were confirmed to cause resistance to T1249, as well as cross-resistance to T20 and C34, but not to the third-generation fusion inhibitor T2635. We also observed substitutions at residues 79 and 90 (Q79E and K90E), which provide modest resistance to T1249 and, interestingly, T2635. Thus, the gp41 amino acid position implicated in T20 resistance (V38 replaced by A, G, or W) is also responsible for T1249 resistance (V38 replaced by E, R, or K). These results indicate that T20 and T1249 exhibit very similar inhibition modes that call for similar but not identical resistance mutations. All T1249-resistant viruses with changes at position 38 are cross resistant to T20, but not vice versa. Furthermore, substitutions at position 38 do not provide resistance to the third-generation inhibitor T2635, while substitution at positions 79 and 90 do, suggesting different resistance mechanisms.

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Primary Human Immunodeficiency Virus Type 1 (HIV-1) Infection during HIV-1 Gag Vaccination

Journal of Virology ◽

10.1128/jvi.01720-07 ◽

2008 ◽

Vol 82 (6) ◽

pp. 2784-2791 ◽

Cited By ~ 7

Author(s):

Arumugam Balamurugan ◽

Martha J. Lewis ◽

Christina M. R. Kitchen ◽

Michael N. Robertson ◽

John W. Shiver ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Dna Vaccine ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Natural Immunity ◽

The Third ◽

Immunodeficiency Virus ◽

Hiv 1 ◽

Ctl Responses

ABSTRACT Vaccination for human immunodeficiency virus type 1 (HIV-1) remains an elusive goal. Whether an unsuccessful vaccine might not only fail to provoke detectable immune responses but also could actually interfere with subsequent natural immunity upon HIV-1 infection is unknown. We performed detailed assessment of an HIV-1 gag DNA vaccine recipient (subject 00015) who was previously uninfected but sustained HIV-1 infection before completing a vaccination trial and another contemporaneously acutely infected individual (subject 00016) with the same strain of HIV-1. Subject 00015 received the vaccine at weeks 0, 4, and 8 and was found to have been acutely HIV-1 infected around the time of the third vaccination. Subject 00016 was a previously HIV-1-seronegative sexual contact who had symptoms of acute HIV-1 infection approximately 2 weeks earlier than subject 00015 and demonstrated subsequent seroconversion. Both individuals reached an unusually low level of chronic viremia (<1,000 copies/ml) without treatment. Subject 00015 had no detectable HIV-1-specific cytotoxic T-lymphocyte (CTL) responses until a borderline response was noted at the time of the third vaccination. The magnitude and breadth of Gag-specific CTL responses in subject 00015 were similar to those of subject 00016 during early chronic infection. Viral sequences from gag, pol, and nef confirmed the common source of HIV-1 between these individuals. The diversity and divergence of sequences in subjects 00015 and 00016 were similar, indicating similar immune pressure on these proteins (including Gag). As a whole, the data suggested that while the gag DNA vaccine did not prime detectable early CTL responses in subject 00015, vaccination did not appreciably impair his ability to contain viremia at levels similar to those in subject 00016.

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Association of human immunodeficiency virus type 1 envelope glycoprotein with particles depends on interactions between the third variable and conserved regions of gp120.

Journal of Virology ◽

10.1128/jvi.67.6.3639-3643.1993 ◽

1993 ◽

Vol 67 (6) ◽

pp. 3639-3643 ◽

Cited By ~ 18

Author(s):

R L Willey ◽

M A Martin

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Envelope Glycoprotein ◽

The Third ◽

Conserved Regions ◽

Immunodeficiency Virus

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Unique Monoclonal Antibody Recognizing the Third Extracellular Loop of CXCR4 Induces Lymphocyte Agglutination and Enhances Human Immunodeficiency Virus Type 1-Mediated Syncytium Formation and Productive Infection

Journal of Virology ◽

10.1128/jvi.75.23.11534-11543.2001 ◽

2001 ◽

Vol 75 (23) ◽

pp. 11534-11543 ◽

Cited By ~ 20

Author(s):

Reiko Tanaka ◽

Atsushi Yoshida ◽

Tsutomu Murakami ◽

Eishi Baba ◽

Julliane Lichtenfeld ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Syncytium Formation ◽

Productive Infection ◽

Extracellular Loop ◽

The Third ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT To increase insight into the structural basis of CXCR4 utilization in human immunodeficiency virus type 1 (HIV-1) infection, a new generation of three monoclonal antibodies (MAbs) was developed in WKA rats. The A80 MAb, which binds an epitope in the third extracellular loop (ECL3) of CXCR4, has unique biologic properties that provide novel insights into CXCR4 function. This agent enhanced syncytium formation in activated human peripheral blood mononuclear cells (PBMC) infected with X4 or R5 and CEM cells infected with X4 HIV-1 strains. Exposure to A80 increased the productive infection of activated CD4+ T cells and CEM cells with R5 and X4 viruses, respectively. This antibody uniquely induced agglutination of PBMC and CEM cells but did not activate calcium mobilization. Agglutination induced by A80 was inhibited by stromal cell-derived factor 1, T22, and phorbol 12-myristate 13-acetate but was not significantly altered by pretreatment of cells with pertussis toxin, wortmannin, or MAbs to LFA-1, ICAM-1, ICAM-2, and ICAM-3. The binding of the A145 and A120 MAbs was mapped to the N-terminal extracellular domain and a conformational epitope involving ECL1 and ECL2, respectively. Both of these MAbs inhibited HIV-1 infection and lacked the novel properties of A80. These results suggest a new role for CXCR4 in homologous lymphocyte adhesion that is ligand independent and in HIV-1 infection.

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