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



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Non-progressors are considered to represent the tail end of the distribution curve of rates of disease progression, and although elite non-progressors are extending this curve even further, disease progression may be inevitable in this rare group of individuals. Recent analyses of the SBBC may support this suggestion.[13,17] However, death from other causes has prevented the establishment of definitive proof of disease progression in some individuals. Two SBBC subjects that did not consent to prospective analysis died from unrelated causes in 1987 and 1994, and the sole SBBC recipient on therapy (C98) has since died from non-HIV causes. Two other elderly subjects also died from non-HIV causes (C18 and C54), but control of viraemia at low levels along with normal CD4 T cell counts suggested there was no evidence for loss LTNP status before death. This leaves the three elite non-progressors from the SBBC described in this study, and one is also advanced in age. One of the elderly Cohort 2 LTNP (with wild-type HIV infection) also died recently from non-HIV causes aged 84 (C122). We may have an opportunity to determine the factors involved in disease progression in the other two Cohort 2 non-progressors (C13 and C53). Both had very low but detectable viraemia, but a recent inversion of CD4 : CD8 T cell ratio in C13 is evident of a change in HIV-induced immune activation. Based on the decline in the proliferative response to p24 preceding this recent increase in viraemia, it is likely that these together signify a transitionary stage toward disease progression in C13.

The p24 proliferative response was the single immune parameter that consistently defined control of viraemia and non-progression. The p24 proliferative response may also be specifically protective, as suggested by a study showing that responses to some Pol antigens were associated with increased viraemia, whereas a protective association was always found in responses to Gag antigens.[35] HIV-specific proliferative responses may also promote CTL proliferation. This was supported by the response to a spike in viraemia in patient C18, where the HIV-specific CD4 and CD8 memory T cell pool increased and were maintained throughout this period (both proliferation and CTL precursor assays measure proliferating antigen-specific memory T cells), whereas effector CTL (ELISPOT-positive cells) peaked then declined as viraemia declined. These data suggest that effective helper T cell function involves proliferation followed by maturation into both effector and costimulatory cells that provide "help" for other lymphocyte functions. Thus, antigen-specific CD8 T cell proliferation may be directly associated with CD4 proliferation to epitopes on the corresponding antigen. It is also possible that loss of protective CD4 and CD8 HIV-specific proliferation may be mediated by a common immunological defect.

The other distinguishing feature of most slow and non-progressor subjects that we have studied is the predominance of Gag CTL, but the SBBC non-progressors were exceptional in having a Pol-dominant CTL response. This observation is unexpected, considering the extensively published role for Gag CTL in controlling viraemia.[20,21,23] Also peculiar to SBBC members, the strongest CTL responses were detected in those with detectable viraemia, and were weaker in subjects with undetectable viraemia.[15] In the non-attenuated HIV-infected non-progressors, strong immunodominant CTL combined with detectable proliferative responses to p24 appears to have contributed to viraemia remaining < 100 copies/ml after 23 years HIV-1 infection in patient C53. The individual with the strongest CTL response was C122, but CTL increased as viraemia increased in this patient, while proliferative responses to Gag p24 declined. Given the predominant CTL response in this subject was directed against an immunodominant HLA B27 restricted p24 epitope, and that there were no immune escape sequences detected at this epitope, it is likely that the decline in the p24-specific proliferative response was the key event that contributed to the failure of CTL to control viraemia, as it is understood that CTL have much reduced functional efficiency in containing viraemia in the absence of helper T cell responses.[24] Another study of HLA B57 positive individuals found no association between disease progression and the strength of CTL responses or the emergence of viral escape mutants at these epitopes, but it was found that viral replicative fitness influenced disease course.[36] The contribution of p24-specific proliferative responses was not investigated in that study.

The neutralising antibody (NAb) response is another immune mechanism that may contribute to long term control of viraemia.[37] We recently analysed viral replicative fitness and the strength of NAb responses, and confirmed that NAb titres in long-term infected subjects were inversely proportional to viral load. However, NAb titres in SBBC members were comparatively weaker, and in parallel with CTL responses, were highest in those with detectable viraemia. The presence of strong Nabs did not prevent some SBBC members from developing signs of disease progression.[38] Hence, we suggest that while broad Nabs might be generated due to a crippled infection they do not prevent disease progression, particularly in the absence of antiviral helper T cell responses.

What is the key factor that sustains a non-progressive disease course, and what initiates the decline in protective immunity after many years of a non-progressive disease course. Could a change in viral pathogenicity overcome this delicate balance between host and virus, or could progressive weakening of the CD4 T cell response by slow virus turnover gradually allow the virus to escape the combined effector mechanisms of the HIV-specific cell-mediated and humoral immune responses? Escape mutants at the B27 epitope KRWIILGLNK have been observed under conditions of high viral load and evolutionary drift,[34] which was likely in C117, but not for both C13 and C122, who had prolonged periods of immune control in the presence of p24 proliferative responses, and very low viraemia up to or beyond the second decade of HIV infection. Disease progression in one SBBC member (C98) and the SBBC infecting donor was associated with the emergence of divergent strains which preceded viral load increases and subsequent changes in immune responses.[39,40] Also, these individuals lacked protective p24 proliferative responses and had detectable viraemia before viral divergence occurred, providing further evidence that effective immune control over viral replication to levels below a putative threshold, may prevent the emergence of escape mutants or fitter variants. Therefore, the common factor in all these observations is the decline or lack of p24 proliferative responses, suggesting that a lack of helper T cell responses may result in a reduced capacity to contain viral replication by other immune effector responses including CTL, independent of the presence of viral escape mutants.


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