Mechanisms of HIV Non-progression; Robust and Sustained CD4+ T-cell Proliferative Responses to P24 Antigen Correlate With Control of Viraemia and Lack of Disease Progression After Long-term Transfusion-acquired HIV-1 Infection

Wayne B. Dyer; John J. Zaunders; Fang Fang Yuan; Bin Wang; Jennifer C. Learmont; Andrew F. Geczy; Nitin K. Saksena; Dale A. McPhee; Paul R. Gorry; John S. Sullivan

Disclosures

Retrovirology 

In This Article

Abstract and Background

Abstract

Background: Elite non-progressors (plasma viral load < 50 copies/ml while antiretroviral naive) constitute a tiny fraction of HIV-infected individuals. After 12 years follow-up of a cohort of 13 long-term non-progressors (LTNP) identified from 135 individuals with transfusion-acquired HIV infection, 5 remained LTNP after 23 to 26 years infection, but only 3 retained elite LTNP status. We examined the mechanisms that differentiated delayed progressors from LTNP in this cohort.
Results: A survival advantage was conferred on 12 of 13 subjects, who had at least one host genetic factor (HLA, chemokine receptor or TLR polymorphisms) or viral attenuating factor (defective nef) associated with slow progression. However, antiviral immune responses differentiated the course of disease into and beyond the second decade of infection. A stable p24-specific proliferative response was associated with control of viraemia and retention of non-progressor status, but this p24 response was absent or declined in viraemic subjects. Strong Gag-dominant cytotoxic T lymphocyte (CTL) responses were identified in most LTNP, or Pol dominant-CTL in those with nef-defective HIV infection. CTL were associated with control of viraemia when combined with p24 proliferative responses. However, CTL did not prevent late disease progression. Individuals with sustained viral suppression had CTL recognising numerous Gag epitopes, while strong but restricted responses to one or two immunodominant epitopes was effective for some time, but failed to contain viraemia over the course of this study. Viral escape mutants at a HLA B27-restricted Gag-p24 epitope were detected in only 1 of 3 individuals, whereas declining or negative p24 proliferative responses occurred in all 3 concurrent with an increase in viraemia.
Conclusion: Detectable viraemia at study entry was predictive of loss of LTNP status and/or disease progression in 6 of 8, and differentiated slow progressors from elite LTNP who retained potent virological control. Sustained immunological suppression of viraemia was independently associated with preserved p24 proliferative responses, regardless of the strength and breadth of the CTL response. A decline in this protective p24 response preceded or correlated with loss of non-progressor status and/or signs of disease progression.

Background

A cohort of blood product recipients with transfusion-acquired HIV (TAHIV) infected between 1981 and 1984 was followed prospectively by the Australian Red Cross Blood Service HIV Lookback Team since 1987. There are individuals in this cohort who have remained asymptomatic for 27 years since infection without antiretroviral therapy; some maintaining plasma HIV RNA levels to below detectable levels and a stable CD4 T cell count, thus retaining elite non-progressor status. Early natural history studies on this and other cohorts suggested that TAHIV infection may result in a shorter time to AIDS than sexually-acquired (SA) HIV infection.[1,2] This observed increase in the rate of disease progression in TAHIV may be due to the higher inoculation volume of blood product compared with the much smaller blood or genital fluid exchange involved in SAHIV infection,[1] as well as the known immunomodulatory effect of transfusion on immune function.[3,4] Age is also an independent predictor for an increased rate of HIV disease progression.[5,6] The bias toward an aged population requiring transfusion is part of the composite disadvantage of transfusion as a route of HIV infection.[1] In addition to HIV infection, survival may be influenced by the underlying medical cause for transfusion. Yet despite these disadvantages, we previously observed a high frequency of non-progression in this TAHIV cohort after 20 years of infection.[7]

Early studies on this cohort of TAHIV patients led to the identification of the Sydney Blood Bank Cohort (SBBC) of long-term survivors,[8] and that an attenuated nef-deleted strain of HIV-1, transmitted from a single donor resulted in slow to non-progression in these individuals.[9] However, after prolonged infection, not all SBBC members maintained non-progressive disease.[10,11,12,13] Although HLA type did not explain non-progression in this group,[14] we have observed differences in CD8 T cell responses that are associated with HLA-dependent epitope recognition,[15] and we have detected increased preservation of helper T cell responses in non-progressors from this cohort.[16,17] In addition to the well described host genetic factors which may prolong non-progression,[7] recent studies have suggested an influence from innate immune mechanisms, including polymorphisms that decrease TLR function thereby reducing immune activation upon exposure to infections diseases,[18] or the FcγRIIA polymorphism (R/R) which is strongly associated with progressive HIV disease as a result of impaired elimination of HIV immune complexes.[19]

While host genetic factors may predispose an individual for delayed disease progression, there is substantial evidence that antiviral T cell responses are required to sustain non-progressor status. Earlier studies have demonstrated an important role for Gag-specific CTL in delaying disease progression.[20,21] Non-progressors that control viraemia in the absence of antiviral therapy also have strong CD4 T cell proliferative responses to the Gag protein p24.[22] Importantly, for Gag CTL to be efficient in killing HIV-infected cells and therefore protective in controlling viraemia, these must also be accompanied by p24-specific T cell proliferative responses.[23,24,25] Appropriate T cell help is also required to achieve maturation and display of effector phenotypes on CTL associated with effective virological control.[26]

To determine how these host genetic and immune factors combined to contribute to prolonged non-progression in our TAHIV cohort, we report here on the current status of the elite non-progressors not on antiretroviral therapy (ART), examining the factors that have influenced disease in the former non-progressors (now on therapy or deceased), and analyse potential mechanisms that have influenced non-progression in this cohort for up to 27 years.

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