A New Simian Model Could Help Finding a HIV Functional Cure
Human Elite Controllers (EC) are considered as a model of HIV infection functional cure; at least, a subset of them who never progress and have undetectable levels of viremia and inflammation.
Research on human EC is, however, restricted to studies of the chronic infection. Samples are collected at random time points, access to tissues is limited, and early events cannot be analyzed.
In a terrific paper (1) published this week, Ronald Veazy group describes the identification of a new animal model of EC, which is supposed to revolutionize our approach towards a functional HIV cure.
The authors report the development of an animal model of elite controlled infection in which control occurs in 100% of cases and thus can be predicted at the stages of infection in which the virus is still actively replicating.
This model is based on rhesus macaques (RM) infection with SIVagm.sab, which is characterized by robust acute viral replication and immune activation, massive acute mucosal CD4+ T cell depletion, followed by complete control of viral replication during the chronic stage and complete recovery of immune injuries.
Consequently, this is a complete different situation of RM infected with SIVmac where only a minority of them become EC.
Twelve RM were intravenously infected with SIVagm.sab92018. During acute infection, they developed lymphadenopathy. One of then developed a rash and 6 of them experienced weight loss and fever.
After 3 months, all RM controlled viral replication and none of them showed any clinical or biological signs of disease progression during follow up.
This status is not due to an impairment of viral replication
Active replication was observed during primary infection with peak plasma levels of 107 to 109 copies/ml by day 10 post infection (p.i.).
Post peak, viral loads continuously declined until they became undetectable (by day 72 to 98 p.i.). SIVagm viral dynamics in the intestine generally paralleled those observed in plasma.
Astonishingly, when anti-gp41 SIVagm antibodies were measured, the authors observed a secoconversion in all animals by day 21 p.i. BUT WITH THE CONTROL OF VIRAL REPLICATION DURING CHRONIC INFECTION, THE ANIMALS SEROREVERTED starting from day 360 p.i.
Anti-SIVagm.sab neutralizing antibodies showed similar dynamics.
This status does not result from limited viral replication in tissues during acute infection
During acute infection, the virus was present at high levels in both lymphoid and non lymphoid tissues. Viral loads dropped by 3 to 4 logs at the set point. During chronic infection, viral replication was generally controlled in all analyzed tissues with very low blips being observed in the mesenteric lymph node, rectum and testis of one animal and in the submandibular lymph node and colon of another.
This status is not due to specific MHC profiles
No correlation was found between a given MHC type and control of SIVagm replication.
This status is not due to an inability of the virus to infect CD4 T cells in different compartments
During the chronic phase, peripheral CD4+ T cells rebounded to preinfection levels starting from day 200 p.i.. Even in lymph nodes, a complete restoration was observed at late time points.
A dramatic (up to 95%) acute depletion of CD4+ T cells occured by day 14-28 p.i. at the immune effector sites in the lamina propria of the intestine. During chronic SIVagm infection, a gradual immune restoration was observed resulting to a complete restoration of the mucosal CD4+ T cells after 4 years p.i.
This status does not result from a peculiar in vivo biology of the virus
No significant deletion in any of the accessory genes was found.
SIVagm.sab92018 has the ability to use both CXCR4 and CCR5 in vitro. However, SIVagm.sab from the plasma during acute infection used only CCR5 as a coreceptor.
CD4 T cell depletion occured in SIVagm-infected RM through the same mechanisms as in pathogenic SIVmac infection of RM
One of the major differences between pathogenic and non pathogenic SIV infections relies on the mechanisms of CD4+ T cell depletion. In pathogenic infection, destruction occurs through direct killing and indirect mechanisms, such as bystander apoptosis. Conversely, in non pathogenic infections, the levels of apoptosis do not significantly change during SIV infection.
In SIVagm-infected RM, increases of both necrosis and apoptosis of GALT CD4+ T cells were demonstrated and bystander apoptosis was a significant contributor to the delay of several months in the restoration of CD4+ T cells after viral control.
A complete restoration of the mucosal immunologic barrier was observed
Microbial translocation, assessed by measuring levels of sCD14, only showed a transient increase, then returned to baseline with the control of apoptosis.
This status is not due to host restriction factors
No correlation was found with APOBEC or TRIM5.
Elite controlled SIVagm infection of RM can be reverted by depletion of CD8+ cells
Anti-CD8 depleting antibodies were used in 3 animals. Prior to CD8 depletion, viral replication was undetectable for 4 years. Post depletion, a rebound in plasma viral loads was observed in all cases. Viral replication was accompanied by depletion of CD4+ T cells in blood and intestine. Interestingly, peripheral CD4+ T cell depletion was abrupt and preceded the rebound of viral replication.
In conclusion, this study shows that acute mucosal CD4+ T cell depletion has no prognostic value for the chronic outcome of infection. Residual apoptosis and immune activation in subjects with undetectable plasma viral load are due to an incomplete control of viral replication.
In SIVagm-infected RM, low levels of viral replication persisted in tissues several months after plasma viral load became undetectable and prevented the control of the apoptosis, microbial translocation and immune activation, hence the immune restoration was quasi inexistant during this time. Conversely, after the achievement of the complete control of virus replication in tissues, apoptosis and immune activation were resolved and normalization of these parameters was followed by complete restoration of the mucosal CD4+ T cells.
"These findings suggest that in human EC, as well as in patients treated with HAART, incomplete immune restoration and persistent elevated levels of immune activation which are observed despite undetectable plasma viral load may be due to very low levels of residual viral replication in tissues" the authors added.
Definitely, this model is a major achievement in the field and for the quest of a functional HIV cure.
Pandrea I, Gaufin T, Gautam R et al. Functional Cure of SIVagm Infection in Rhesus Macaques Results in Complete Recovery of CD4+ T Cells and Is Reverted by CD8+ Cell Depletion. PLoS Pathogens 2011; 7 (8): e1002170
Key words: HIV Elite Controllers, HIV animal models, HIV cure, HIV functional cure