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. 2001 Nov;75(21):10187-99.
doi: 10.1128/JVI.75.21.10187-10199.2001.

Role of CD8(+) lymphocytes in control of simian immunodeficiency virus infection and resistance to rechallenge after transient early antiretroviral treatment

J D Lifson  1 , J L Rossio, M Piatak Jr, T Parks, L Li, R Kiser, V Coalter, B Fisher, B M Flynn, S Czajak, V M Hirsch, K A Reimann, J E Schmitz, J Ghrayeb, N Bischofberger, M A Nowak, R C Desrosiers, D Wodarz
Affiliations

Role of CD8(+) lymphocytes in control of simian immunodeficiency virus infection and resistance to rechallenge after transient early antiretroviral treatment

J D Lifson et al. J Virol. 2001 Nov.

Abstract

Transient antiretroviral treatment with tenofovir, (R)-9-(2-phosphonylmethoxypropyl)adenine, begun shortly after inoculation of rhesus macaques with the highly pathogenic simian immunodeficiency virus (SIV) isolate SIVsmE660, facilitated the development of SIV-specific lymphoproliferative responses and sustained effective control of the infection following drug discontinuation. Animals that controlled plasma viremia following transient postinoculation treatment showed substantial resistance to subsequent intravenous rechallenge with homologous (SIVsmE660) and highly heterologous (SIVmac239) SIV isolates, up to more than 1 year later, despite the absence of measurable neutralizing antibody. In some instances, resistance to rechallenge was observed despite the absence of detectable SIV-specific binding antibody and in the face of SIV lymphoproliferative responses that were low or undetectable at the time of challenge. In vivo monoclonal antibody depletion experiments demonstrated a critical role for CD8(+) lymphocytes in the control of viral replication; plasma viremia rose by as much as five log units after depletion of CD8(+) cells and returned to predepletion levels (as low as <100 copy Eq/ml) as circulating CD8(+) cells were restored. The extent of host control of replication of highly pathogenic SIV strains and the level of resistance to heterologous rechallenge achieved following transient postinoculation treatment compared favorably to the results seen after SIVsmE660 and SIVmac239 challenge with many vaccine strategies. This impressive control of viral replication was observed despite comparatively modest measured immune responses, less than those often achieved with vaccination regimens. The results help establish the underlying feasibility of efforts to develop vaccines for the prevention of AIDS, although the exact nature of the protective host responses involved remains to be elucidated.

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Figures

FIG. 1
FIG. 1
Control of viremia, SIV lymphoproliferative responses, and resistance to early and late homologous SIV rechallenge. Plasma SIV RNA levels (triangles; open symbols prior to seroconversion, solid symbols after seroconversion [antibody status not evaluated at every time point]) and SIV-specific lymphoproliferative responses (open diamonds) are shown for macaques infected intravenously with 30 MID50 of SIVsmE660 and then transiently treated with tenofovir to block viral replication. Black arrows indicate initial inoculation and subsequent homologous rechallenges. (A to E) The interval of drug treatment is indicated by the shaded box and consisted of 28 days, beginning 24 h p.i. in Rh 120 (A), Rh 300 (B), and Rh 009 (C), or either 28 days (Rh 155) (D) or 63 days (Rh 092) (E) of treatment, beginning 72 h p.i. (F) Results for a representative, contemporaneously inoculated, SIV-naive, untreated control animal, for each separate challenge. Note the control of plasma viremia and increased lymphoproliferative responses for animals receiving early transient treatment relative to control animals. Dotted line indicates threshold sensitivity for RNA assay, 300 copy Eq/ml (early time points) or 100 copy Eq/ml (later time points); dashed line indicates threshold for positive lympoproliferative responses, stimulation index (S.I.) ≥ 2.5.
FIG. 2
FIG. 2
Humoral responses. Results shown are reciprocal titers for SIV-binding antibody (determined by ELISA; open triangles, range from <160 to >40,000) and neutralizing antibody against SIVsmE660 (black bars), SIVmac239 (white bars), and neutralization-sensitive culture-adapted SIVmac251 (gray bars) for animals Rh 120 (A), Rh 300 (B), Rh 009 (C), Rh 092 (D), and Rh 155 (E) and representative untreated, SIVsmE660-infected (Rh 128 and Rh 226) or SIVmac239-infected (Rh 405) control animals (F). Dashed lines indicate assay threshold levels (160 for ELISA binding antibody [short black dashes], 20 for SIV smE660 neutralizing antibody [short gray dashes], and 40 for SIVmac239 and SIVmac251 neutralizing antibody [long black dashes]), Jagged-ended gray bars indicate an SIVmac251 reciprocal neutralizing titer of >5,000. For panels A (Rh 120) and B (Rh 300); 1, preinoculation; 2, last day on PMPA treatment; 3, pre-early SIVsmE660 rechallenge; 4, 2 weeks post-early SIVsmE660 rechallenge; 5, 10 weeks post-early SIVsmE660 rechallenge; 6, pre-late SIVsmE660 rechallenge; 7, 2 weeks post-late SIVsmE660 rechallenge; 8, 10 weeks post-late SIVsmE660 rechallenge; 9, pre-CD8 depletion; 10, 2 weeks post-CD8 depletion; 11, pre-late SIVmac239 rechallenge; 12, 2 weeks post-SIVmac239 rechallenge; 13, 4 weeks post-SIVmac239 rechallenge. For panels C (Rh 009), D (Rh 092), and E (Rh 155): 1, preinoculation; 2, last day on PMPA treatment, 3, 2 weeks post-PMPA treatment; 4, pre-early SIVsmE660 rechallenge; 5, pre-late SIVsmE660 rechallenge; 6, 2 weeks post-late SIVsmE660 rechallenge; 7, pre-SIVmac239 rechallenge; 8, 2 weeks post-SIVmac239 rechallenge; 9, pre-CD8 depletion; 10, 2 weeks post-CD8 depletion; 11, 3 weeks post-CD8 depletion. For panel F, bleeds are as labelled. Open triangles show ELISA binding-antibody titers. Both SIVsmE660 and SIVmac239 are very difficult to neutralize; neutralizing titers in chronically infected animals are generally <1:40 and are often not measurable (Desrosiers et al., unpublished). For chronically SIV-infected macaques, neutralizing titers against the cell line-adapted SIVmac251 are typically in the range of 1:10,000.
FIG. 3
FIG. 3
Results for in vivo depletion of CD8+ cells (doses indicated by small open arrows) and heterologous (SIVmac239; 100 MID50 intravenously) virus rechallenge (large open arrow) in animal Rh 120. (A) Plasma viral load (triangles) and viral genotype (bars; SIVsmE660 [grey] or SIVmac239 [white]), based on characterization of at least 20 independent clones derived from RT-PCR-amplified plasma viral RNA for each indicated time point. (B) Absolute CD3+ CD4+ cell counts per microliter of of peripheral blood (circles) and SIV-specific proliferative responses (diamonds). (C) Absolute CD3+ CD8+ cell counts per microliter of peripheral blood (circles), SIV-specific CD8+ cells/105 total CD3+ CD8+ cells (diamonds), and SIV-inducible MIP-1β secretion (grey bars). LNMC from a biopsy specimen obtained after 2 of 3 doses of anti-CD8 MAb showed 15% residual CD3+ CD8+ cells, compared to 4% in matched PBMC. IFN-γ, gamma interferon.
FIG. 4
FIG. 4
Results for in vivo depletion of CD8+ cells (doses indicated by small open arrows) and heterologous (SIVmac239; 100 MID50 intravenously) virus rechallenge (large open arrow) in animal Rh 300. Graphing conventions are as for Fig. 3. LNMC from a biopsy specimen obtained after two of three doses of anti-CD8 MAb showed 9% residual CD3+ CD8+ cells, compared to 3% in matched PBMC.
FIG. 5
FIG. 5
Results for heterologous (SIVmac239; 100 MID50 intravenously) virus rechallenge (large open arrow) and in vivo depletion of CD8+ cells (doses indicated by small open arrows) in animal Rh 009. Note the reversal of the order of anti-CD8 MAb depletion and heterologous rechallenge, relative to animals Rh 120 and Rh 300 (Fig. 3 and 4). Graphing conventions are as for Fig. 3. LNMC from a biopsy specimen obtained after two of three doses of anti-CD8 MAb showed 24% residual CD3+ CD8+ cells, compared to 6% in matched PBMC.
FIG. 6
FIG. 6
Results for heterologous (SIVmac239; 100 MID50 intravenously) virus rechallenge (large open arrow) and in vivo depletion of CD8+ cells (doses indicated by small open arrows) in animal Rh 092. Graphing conventions are as for Fig. 3. LNMC from a biopsy specimen obtained after two of three doses of anti-CD8 MAb showed 14% residual CD3+ CD8+ cells, compared to 1% in matched PBMC.
FIG. 7
FIG. 7
Results for heterologous (SIVmac239; 100 MID50 intravenously) virus rechallenge (large open arrow) and in vivo depletion of CD8+ cells (doses indicated by small open arrows) in animal Rh 155. Graphing conventions are as for Fig. 3. LNMC from a biopsy specimen obtained after two of three doses of anti-CD8 MAb showed 14% residual CD3+ CD8+ cells, compared to 3% in matched PBMC.
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