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Longitudinal study of primary HIV-1 isolates in drug-naïve individuals reveals the emergence of variants sensitive to anti-HIV-1 monoclonal antibodies.

Haldar B, Burda S, Williams C, Heyndrickx L, Vanham G, Gorny MK, Nyambi P - PLoS ONE (2011)

Bottom Line: Virus collected from a patient obtained 31 months later, evolved increased sensitivity to anti-V2, anti-V3, and anti-CD4bd mAbs.Anti-V3 mAbs exhibited the most breadth and potency in neutralizing the evolving viruses.Sequence analysis of the envelope regions revealed amino acid conservation within the V3 loop, while most of the changes identified occurred outside the core epitopes and in particular within the C3 region; these may account for increased neutralization sensitivity.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, New York University School of Medicine, New York, New York, United States of America.

ABSTRACT
To study how virus evolution affects neutralization sensitivity and to determine changes that occur in and around epitopes, we tested the ability of 13 anti-HIV-1 gp120 (anti-V2, anti-V3, anti-CD4bd and anti-carbohydrate) human monoclonal antibodies (mAbs) to neutralize sequential viruses obtained from five HIV-1 chronically infected drug naïve individuals. Overall, primary viruses collected from patients at first visit were resistant to neutralization by all anti-HIV-1 mAbs with the exception of one virus sensitive to IgG1b12. Four of the five patients' viruses evolved increased sensitivity to neutralization by anti-V3 mAbs. Virus collected from a patient obtained 31 months later, evolved increased sensitivity to anti-V2, anti-V3, and anti-CD4bd mAbs. Furthermore, the anti-V2 and anti-CD4bd mAbs also exhibited increased neutralization capacities against virus collected from a patient 29 months later. Of the seven anti-V3 mAbs, five showed increased potency to neutralize the evolved virus from a patient collected after 11 months, and three exhibited increased potency against viruses from two patients collected 29 and 36 months later. Anti-V3 mAbs exhibited the most breadth and potency in neutralizing the evolving viruses. Sequence analysis of the envelope regions revealed amino acid conservation within the V3 loop, while most of the changes identified occurred outside the core epitopes and in particular within the C3 region; these may account for increased neutralization sensitivity. These studies demonstrate that in vivo, HIV-1 can evolve increased neutralization sensitivity to mAbs and that the spectrum of neutralization capacities by mAbs can be broader when studied in longitudinal analysis.

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Related in: MedlinePlus

CD4 profile of HIV-1 infected study subjects.All the study subjects were asymptomatic. CD4 counts were determined by FACScan.
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pone-0017253-g001: CD4 profile of HIV-1 infected study subjects.All the study subjects were asymptomatic. CD4 counts were determined by FACScan.

Mentions: A portion of the sequential blood samples were collected from the five HIV-1-infected subjects and used to determine the CD4 cell counts by FACScan. Their CD4 profiles are shown in figure 1 and reveal that all these subjects studied were asymptomatic during the study period and were naive to antiretroviral drugs. At the start of the study, the CD4 counts of three study subjects (ITM27, ITM39, and NYU104) ranged between 411 and 437 cells/mm3, while the CD4 counts of two study subjects (ITM60 and 3506) was 1031 and 993 cells/mm3. The CD4 counts of ITM60 and NYU104 declined to 671 and 253 cells/mm3, while the CD4 counts of two study subjects (ITM39 and 3506) stayed relatively stable over time (499 and 750 cells/mm3), respectively. It was noted that the CD4 T cell count of subject ITM27 increased from 415 to 767 cells/mm3. Viruses isolated from a portion of the blood sample that was used for CD4 count determination were used for the neutralization studies described below.


Longitudinal study of primary HIV-1 isolates in drug-naïve individuals reveals the emergence of variants sensitive to anti-HIV-1 monoclonal antibodies.

Haldar B, Burda S, Williams C, Heyndrickx L, Vanham G, Gorny MK, Nyambi P - PLoS ONE (2011)

CD4 profile of HIV-1 infected study subjects.All the study subjects were asymptomatic. CD4 counts were determined by FACScan.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3044167&req=5

pone-0017253-g001: CD4 profile of HIV-1 infected study subjects.All the study subjects were asymptomatic. CD4 counts were determined by FACScan.
Mentions: A portion of the sequential blood samples were collected from the five HIV-1-infected subjects and used to determine the CD4 cell counts by FACScan. Their CD4 profiles are shown in figure 1 and reveal that all these subjects studied were asymptomatic during the study period and were naive to antiretroviral drugs. At the start of the study, the CD4 counts of three study subjects (ITM27, ITM39, and NYU104) ranged between 411 and 437 cells/mm3, while the CD4 counts of two study subjects (ITM60 and 3506) was 1031 and 993 cells/mm3. The CD4 counts of ITM60 and NYU104 declined to 671 and 253 cells/mm3, while the CD4 counts of two study subjects (ITM39 and 3506) stayed relatively stable over time (499 and 750 cells/mm3), respectively. It was noted that the CD4 T cell count of subject ITM27 increased from 415 to 767 cells/mm3. Viruses isolated from a portion of the blood sample that was used for CD4 count determination were used for the neutralization studies described below.

Bottom Line: Virus collected from a patient obtained 31 months later, evolved increased sensitivity to anti-V2, anti-V3, and anti-CD4bd mAbs.Anti-V3 mAbs exhibited the most breadth and potency in neutralizing the evolving viruses.Sequence analysis of the envelope regions revealed amino acid conservation within the V3 loop, while most of the changes identified occurred outside the core epitopes and in particular within the C3 region; these may account for increased neutralization sensitivity.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, New York University School of Medicine, New York, New York, United States of America.

ABSTRACT
To study how virus evolution affects neutralization sensitivity and to determine changes that occur in and around epitopes, we tested the ability of 13 anti-HIV-1 gp120 (anti-V2, anti-V3, anti-CD4bd and anti-carbohydrate) human monoclonal antibodies (mAbs) to neutralize sequential viruses obtained from five HIV-1 chronically infected drug naïve individuals. Overall, primary viruses collected from patients at first visit were resistant to neutralization by all anti-HIV-1 mAbs with the exception of one virus sensitive to IgG1b12. Four of the five patients' viruses evolved increased sensitivity to neutralization by anti-V3 mAbs. Virus collected from a patient obtained 31 months later, evolved increased sensitivity to anti-V2, anti-V3, and anti-CD4bd mAbs. Furthermore, the anti-V2 and anti-CD4bd mAbs also exhibited increased neutralization capacities against virus collected from a patient 29 months later. Of the seven anti-V3 mAbs, five showed increased potency to neutralize the evolved virus from a patient collected after 11 months, and three exhibited increased potency against viruses from two patients collected 29 and 36 months later. Anti-V3 mAbs exhibited the most breadth and potency in neutralizing the evolving viruses. Sequence analysis of the envelope regions revealed amino acid conservation within the V3 loop, while most of the changes identified occurred outside the core epitopes and in particular within the C3 region; these may account for increased neutralization sensitivity. These studies demonstrate that in vivo, HIV-1 can evolve increased neutralization sensitivity to mAbs and that the spectrum of neutralization capacities by mAbs can be broader when studied in longitudinal analysis.

Show MeSH
Related in: MedlinePlus