Loss of virus-specific CD4+ T cells with increases in viral loads in the chronic phase after vaccine-based partial control of primary simian immunodeficiency virus replication in macaques
Virus-specific cellular immune responses play an important role in the control of immunodeficiency virus replication. However, preclinical trials of vaccines that induce virus-specific cellular immune responses have failed to contain simian immunodeficiency virus (SIV) replication in macaques. A defective provirus DNA vaccine system that efficiently induces virus-specific CD8+ T-cell responses has previously been developed. The vaccinated macaques showed reduced viral loads, but failed to contain SIVmac239 replication. In this study, macaques that showed partial control of SIV replication were followed up to see if or how they lost this control in the chronic phase. Two of them showed increased viral loads about 4 or 8 months after challenge and finally developed AIDS. Analysis of SIV-specific T-cell levels by detection of SIV-specific gamma interferon (IFN-γ) production revealed that these two macaques maintained SIV-specific CD8+ T cells, even after loss of control, but lost SIV-specific CD4+ T cells when plasma viral loads increased. The remaining macaque kept viral loads at low levels and maintained SIV-specific CD4+ T cells, as well as CD8+ T cells, for more than 3 years. Additional analysis using macaques vaccinated with a Gag-expressing Sendai virus vector also found loss of viraemia control, with loss of SIV-specific CD4+ T cells in the chronic phase of SIV infection. Thus, SIV-specific CD4+ T cells that were able to produce IFN-γ in response to SIV antigens were preserved by the vaccine-based partial control of primary SIV replication, but were lost with abrogation of control in the chronic phase.
AlbrittonL. M.,
TsengL.,
ScaddenD.,
CunninghamJ. M.1989; A putative murine ecotropic retrovirus receptor gene encodes a multiple membrane-spanning protein and confers susceptibility to virus infection. Cell 57:659–666[CrossRef]
AmaraR. R.,
VillingerF.,
AltmanJ. D.19 other authors2001; Control of a mucosal challenge and prevention of AIDS in rhesus macaques by a multiprotein DNA/MVA vaccine. Science 292:69–74[CrossRef]
AppayV.,
NixonD. F.,
DonahoeS. M.13 other authors2000; HIV-specific CD8+ T cells produce antiviral cytokines but are impaired in cytolytic function. J Exp Med 192:63–76[CrossRef]
BarouchD. H.,
SantraS.,
SchmitzJ. E.26 other authors2000; Control of viremia and prevention of clinical AIDS in rhesus monkeys by cytokine-augmented DNA vaccination. Science 290:486–492[CrossRef]
BorrowP.,
LewickiH.,
HahnB. H.,
ShawG. M.,
OldstoneM. B. A.1994; Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol 68:6103–6110
HamannD.,
BaarsP. A.,
RepM. H. G.,
HooibrinkB.,
Kerkhof-GardeS. R.,
KleinM. R.,
van LierR. A. W.1997; Phenotypic and functional separation of memory and effector human CD8+ T cells. J Exp Med 186:1407–1418[CrossRef]
HarariA.,
PetitpierreS.,
VallelianF.,
PantaleoG.2004; Skewed representation of functionally distinct populations of virus-specific CD4 T cells in HIV-1-infected subjects with progressive disease: changes after antiretroviral therapy. Blood 103:966–972
HortonH.,
VogelT. U.,
CarterD. K.15 other authors2002; Immunization of rhesus macaques with a DNA prime/modified vaccinia virus Ankara boost regimen induces broad simian immunodeficiency virus (SIV)-specific T-cell responses and reduces initial viral replication but does not prevent disease progression following challenge with pathogenic SIVmac239. J Virol 76:7187–7202[CrossRef]
IyasereC.,
TiltonJ. C.,
JohnsonA. J.13 other authors2003; Diminished proliferation of human immunodeficiency virus-specific CD4+ T cells is associated with diminished interleukin-2 (IL-2) production and is recovered by exogenous IL-2. J Virol 77:10900–10909[CrossRef]
JinX.,
BauerD. E.,
TuttletonS. E.11 other authors1999; Dramatic rise in plasma viremia after CD8+ T cell depletion in simian immunodeficiency virus-infected macaques. J Exp Med 189:991–998[CrossRef]
KanoM.,
MatanoT.,
NakamuraH.,
TakedaA.,
KatoA.,
AriyoshiK.,
MoriK.,
SataT.,
NagaiY.2000; Elicitation of protective immunity against simian immunodeficiency virus infection by a recombinant Sendai virus expressing the Gag protein. AIDS 14:1281–1282[CrossRef]
KatoA.,
SakaiY.,
ShiodaT.,
KondoT.,
NakanishiM.,
NagaiY.1996; Initiation of Sendai virus multiplication from transfected cDNA or RNA with negative or positive sense. Genes Cells 1:569–579[CrossRef]
KestlerH.,
KodamaT.,
RinglerD.8 other authors1990; Induction of AIDS in rhesus monkeys by molecularly cloned simian immunodeficiency virus. Science 248:1109–1112[CrossRef]
KostenseS.,
OggG. S.,
MantingE. H.8 other authors2001; High viral burden in the presence of major HIV-specific CD8+ T cell expansions: evidence for impaired CTL effector function. Eur J Immunol 31:677–686[CrossRef]
KoupR. A.,
SafritJ. T.,
CaoY.,
AndrewsC. A.,
McLeodG.,
BorkowskyW.,
FarthingC.,
HoD. D.1994; Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol 68:4650–4655
MatanoT.,
ShibataR.,
SiemonC.,
ConnorsM.,
LaneH. C.,
MartinM. A.1998; Administration of an anti-CD8 monoclonal antibody interferes with the clearance of chimeric simian/human immunodeficiency virus during primary infections of rhesus macaques. J Virol 72:164–169
MatanoT.,
KanoM.,
OdawaraT.,
NakamuraH.,
TakedaA.,
MoriK.,
SatoT.,
NagaiY.2000; Induction of protective immunity against pathogenic simian immunodeficiency virus by a foreign receptor-dependent replication of an engineered avirulent virus. Vaccine 18:3310–3318[CrossRef]
MatanoT.,
KanoM.,
NakamuraH.,
TakedaA.,
NagaiY.2001; Rapid appearance of secondary immune responses and protection from acute CD4 depletion after a highly pathogenic immunodeficiency virus challenge in macaques vaccinated with a DNA prime/Sendai virus vector boost regimen. J Virol 75:11891–11896[CrossRef]
MiguelesS. A.,
LaboricoA. C.,
ShupertW. L.11 other authors2002; HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat Immunol 3:1061–1068[CrossRef]
OggG. S.,
JinX.,
BonhoefferS.12 other authors1998; Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA. Science 279:2103–2106[CrossRef]
RoseN. F.,
MarxP. A.,
LuckayA.7 other authors2001; An effective AIDS vaccine based on live attenuated vesicular stomatitis virus recombinants. Cell 106:539–549[CrossRef]
RosenbergE. S.,
BillingsleyJ. M.,
CaliendoA. M.,
BoswellS. L.,
SaxP. E.,
KalamsS. A.,
WalkerB. D.1997; Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 278:1447–1450[CrossRef]
SallustoF.,
LenigD.,
ForsterR.,
LippM.,
LanzavecchiaA.1999; Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 401:708–712[CrossRef]
SchmitzJ. E.,
KurodaM. J.,
SantraS.13 other authors1999; Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 283:857–860[CrossRef]
VogelT. U.,
AllenT. M.,
AltmanJ. D.,
WatkinsD. I.2001; Functional impairment of simian immunodeficiency virus-specific CD8+ T cells during the chronic phase of infection. J Virol 75:2458–2461[CrossRef]
VossG.,
NickS.,
Stahl-HennigC.,
RitterK.,
HunsmannG.1992; Generation of macaque B lymphoblastoid cell lines with simian Epstein-Barr-like viruses: transformation procedure, characterization of the cell lines and occurrence of simian foamy virus. J Virol Methods 39:185–195[CrossRef]
Loss of virus-specific CD4+ T cells with increases in viral loads in the chronic phase after vaccine-based partial control of primary simian immunodeficiency virus replication in macaques