Generation of Neutralizing Antibodies and Divergence of SIVmac239 in Cynomolgus Macaques Following Short-Term Early Antiretroviral Therapy

Human immunodeficiency virus type 2 (HIV-2)-infected individuals develop immunodeficiency with a considerable delay andtransmit the virus at rates lower than HIV-1-infected persons. Conceivably, comparative studies on the immune responsiveness of HIV-1-and HIV-2-infected hosts may help to explain the differences in pathogenesis and transmission between the two types of infection. Previous studies have shown that the neutralizing antibody response is more potent and broader in HIV-2 than in HIV-1 infection. In the present study, we have examined further the function of the humoral immune response and studied the effect of complement on the antiviral activity of plasma from singly HIV-1-or HIV-2-infected individuals, as well as HIV-1/ HIV-2 dually infected individuals. The neutralization and antibody-dependent complement-mediated inactivation of HIV-1 and HIV-2 isolates were tested in a plaque reduction assay using U87.CD4.CCR5 cells. The results showed that the addition of complement increased intratype antiviral activities of both HIV-1 and HIV-2 plasma samples, although the complement effect was more pronounced with HIV-2 than HIV-1 plasma. Using an area-under-the-curve (AUC)-based readout, multivariate statistical analysis confirmed that the type of HIV infection was independently associated with the magnitude of the complement effect. The analyses carried out with purified IgG indicated that the complement effect was largely exerted through the classical complement pathway involving IgG in both HIV-1 and HIV-2 infections. In summary, these findings suggest that antibody binding to HIV-2 structures facilitates the efficient use of complement and thereby may be one factor contributing to a strong antiviral activity present in HIV-2 infection.

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“…Purified IgGs were kept at Ϫ80°C until use. The yield of IgG was analyzed by an in-house ELISA as described previously (10,35).…”

Section: Methodsmentioning

confidence: 99%

Effect of Complement on HIV-2 Plasma Antiviral Activity Is Intratype Specific and Potent

Şahin

Holmgren

Sheik-Khalil

et al. 2013

J Virol

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“…To estimate the impact of this source of uncertainty, we performed a similar analysis on n ϭ 11 longitudinal data sets from a study of simian immunodeficiency virus (SIV) env evolution in macaques experimentally infected by a known inoculum of SIVmac239 (43). If sequences diverged rapidly from the inoculum As entropy of data set increases, the difference between the error rates of the phylogenetic and naive methods increases, in the direction of the phylogenetic method having a lower error rate.…”

Section: Errors Within Immunologically Relevant Positions Errors Occmentioning

confidence: 99%

An Evaluation of Phylogenetic Methods for Reconstructing Transmitted HIV Variants using Longitudinal Clonal HIV Sequence Data

McCloskey

Liang

Harrigan

et al. 2014

J Virol

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A population of human immunodeficiency virus (HIV) within a host often descends from a single transmitted/founder virus. The high mutation rate of HIV, coupled with long delays between infection and diagnosis, make isolating and characterizing this strain a challenge. In theory, ancestral reconstruction could be used to recover this strain from sequences sampled in chronic infection; however, the accuracy of phylogenetic techniques in this context is unknown. To evaluate the accuracy of these methods, we applied ancestral reconstruction to a large panel of published longitudinal clonal and/or single-genome-amplification HIV sequence data sets with at least one intrapatient sequence set sampled within 6 months of infection or seroconversion (n ‫؍‬ 19,486 sequences, median [interquartile range] ‫؍‬ 49 [20 to 86] sequences/set). The consensus of the earliest sequences was used as the best possible estimate of the transmitted/founder. These sequences were compared to ancestral reconstructions from sequences sampled at later time points using both phylogenetic and phylogeny-naive methods. Overall, phylogenetic methods conferred a 16% improvement in reproducing the consensus of early sequences, compared to phylogeny-naive methods. This relative advantage increased with intrapatient sequence diversity (P < 10 ؊5 ) and the time elapsed between the earliest and subsequent samples (P < 10 ؊5 ). However, neither approach performed well for reconstructing ancestral indel variation, especially within indel-rich regions of the HIV genome. Although further improvements are needed, our results indicate that phylogenetic methods for ancestral reconstruction significantly outperform phylogeny-naive alternatives, and we identify experimental conditions and study designs that can enhance accuracy of transmitted/founder virus reconstruction. IMPORTANCEWhen HIV is transmitted into a new host, most of the viruses fail to infect host cells. Consequently, an HIV infection tends to be descended from a single "founder" virus. A priority target for the vaccine research, these transmitted/founder viruses are difficult to isolate since newly infected individuals are often unaware of their status for months or years, by which time the virus population has evolved substantially. Here, we report on the potential use of evolutionary methods to reconstruct the genetic sequence of the transmitted/founder virus from its descendants at later stages of an infection. These methods can recover this ancestral sequence with an overall error rate of about 2.3%-about 15% more information than if we had ignored the evolutionary relationships among viruses. Although there is no substitute for sampling infections at earlier points in time, these methods can provide useful information about the genetic makeup of transmitted/founder HIV.

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“…13,32 Briefly, plates were coated overnight with AffiniPure goat antihuman IgG (20 lg/ml) ( Jackson Immunotech, Marseille, France). Alkaline phosphatase-conjugated antihuman IgG (diluted to 1:5,000) ( Jackson Immunotech, Marseille, France) was used as a detection antibody and human IgG (R&D Systems, Minneapolis, MN) was used as a standard.…”

Section: Assessment Of Igg and Iga Levelsmentioning

confidence: 99%

“…32 In brief, GHOST(3)-CCR5 cells were maintained in Dulbecco's modified Eagle's medium (DMEM; GIBCO) (Life Technologies, Paisley, UK) complemented with 7.5% fetal calf serum (FCS) and 10,000 IU/ml penicillinstreptomycin (Invitrogen, Carlsbad, CA) in 25-cm 2 culture flasks and split twice a week at a ratio of 1:15-20. Briefly, virus stocks and plasma Ig were mixed and diluted in DMEM infection medium, i.e., complete DMEM medium supplemented with 2 lg/ml polybrene (Sigma Aldrich, St. Louis, MO), such that the final virus concentration gave 10-40 fluorescent plaque-forming units (PFU) per well and the final Ig concentrations corresponded to plasma Ig levels (starting at an 1:20 plasma dilution).…”

Section: Neutralization Assay Using Ghost(3)-ccr5 Cellsmentioning

confidence: 99%

Frequent Intratype Neutralization by Plasma Immunoglobulin A Identified in HIV Type 2 Infection

Şahin

Månsson

Palm

et al. 2013

AIDS Research and Human Retroviruses

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Generation of Neutralizing Antibodies and Divergence of SIVmac239 in Cynomolgus Macaques Following Short-Term Early Antiretroviral Therapy

Cited by 10 publications

References 70 publications

Effect of Complement on HIV-2 Plasma Antiviral Activity Is Intratype Specific and Potent

Effect of Complement on HIV-2 Plasma Antiviral Activity Is Intratype Specific and Potent

An Evaluation of Phylogenetic Methods for Reconstructing Transmitted HIV Variants using Longitudinal Clonal HIV Sequence Data

Frequent Intratype Neutralization by Plasma Immunoglobulin A Identified in HIV Type 2 Infection

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