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. 2011 Mar 30;412(1):110-6.
doi: 10.1016/j.virol.2010.12.044. Epub 2011 Jan 26.

Pol as a target for antibody dependent cellular cytotoxicity responses in HIV-1 infection

Gamze Isitman  1 , Amy W Chung, Marjon Navis, Stephen J Kent, Ivan Stratov
Affiliations

Pol as a target for antibody dependent cellular cytotoxicity responses in HIV-1 infection

Gamze Isitman et al. Virology. .

Abstract

Antibody-dependent cellular cytotoxicity (ADCC) may assist in preventing HIV or delaying disease progression. Most prior studies have analysed Env-specific ADCC responses. We hypothesized that effective ADCC-based immunity may target conserved internal viral proteins such as Pol. We analysed the ability overlapping Pol peptides to induce activation of NK cells via ADCC. We prospectively studied ADCC responses in 83 HIV+ subjects followed for 3 years. Pol peptides were commonly targeted by ADCC responses in these chronically infected subjects (in 32 of the 83 subjects). However, Pol-specific ADCC responses declined over time and did not correlate with delayed HIV progression, measured by either baseline CD4 T cells, CD4 T cell loss over time, baseline viral load or the need to start antiretroviral therapy. Although Pol is frequently targeted by ADCC in HIV+ subjects, the strength or specificity of Pol-specific ADCC responses needs to be modulated to be effective in delaying HIV progression.

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Figures

Figure 1
Figure 1. Flowchart of Pol-specific ADCC studies
83 Subjects were initially tested for Pol-specific ADCC responses, 32 showed a positive Pol response. Further mapping of these 32 subjects was then undertaken.
Figure 2
Figure 2. Intracellular cytokine staining ADCC assay and mapping process
A. Gating strategy: lymphocytes from all cells identified and isolated CD3- cells to allow assessment of CD2+ and CD56+ NK cells expressing IFN? B. Subject response to Pol, Pol pool 1–124 and 125–249, mapped to Pol pool 231–249 and fine mapped to Pol peptide Pol 233. Responses for DMSO, Rev, Pol pool 126–146, and Pol 232 are included as irrelevant peptides or pools indicating negative ADCC responses.
Figure 3
Figure 3. Env, Gag and Pol specific ADCC responses
Initial ADCC responses to Pol were identified when ADCC responses were mapped for HIV proteins (Env, Gag and Pol). Significant ADCC responses for env were ascertained as well as for Pol 1 and or Pol 2 by a number of subjects.
Figure 4
Figure 4. Correlation of Pol-specific ADCC responses with HIV progression
Correlation of Pol responses, NK cells expressing IFN? and CD107a to A. viral loads and B. CD4 T cell at recruitment to the study were undertaken. No correlation was evident with all parameters analysed against Pol-specific ADCC responses. C. The unpaired t test was used to assess the relationship between the loss of CD4 T cell (CD4 count slope) over time and whether or not subjects had a detectable Pol-specific ADCC response. The decline in CD4 T cell count over time did not correlate with the presence of an ADCC response to Pol. D. The effects of ART on subjects with a response to Pol were also calculated. Of the subjects, who progressed to require ART, 45% were Pol responders and 31% of ART naïve subjects were also responding to Pol (P=0.52).
Figure 5
Figure 5. Changes in Pol-specific ADCC responses over time
A decline in Pol-specific ADCC responses over time occurred in the majority of subjects.
See this image and copyright information in PMC

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