Zephyr Foundation

Australian researchers have evaluated several potential mechanisms that may contribute to conferring long term non-progression in HIV infection.  The reasons why some individuals can control HIV progression better than others remain under investigation.  Wayne B. Dyer and colleagues in Sydney, Australia, evaluated the blood from a group of study patients with transfusion-acquired HIV infection.  Within this group, 13 patients were identified as LTNPs.  Over the next 12 years, 5 of the study group members retained their LTNP status even after 23 to 26 years infection, but only 3 retained a status of elite LTNP. The researchers examined multiple potential mechanisms that could have differentiated the delayed progressors from elite LTNPs in this study group.

The study began in 1994 when 13 LTNP patients were identified from group of individuals that became HIV infected by blood transfusion.  The guidelines for classifying LTNP consisted of the following:   at least 10 years of infection, stable CD4 T cell counts of greater than 500 cells/μl, and no history of ART. During the course of the study, some individuals were reclassified as slow progressors when any of the following events were recorded: a consistent decline in CD4 T cell counts below 500/μl, the patient started ART, and after viral loads became measurable (>5000 copies/ml). Elite non-progressors were defined by viremia suppressed to <50 copies/ml with CD4 T cell numbers above 500. Disease progression was defined by a CD4 T cell count of 100,000 copies/ml.

The researchers evaluated the viral sequences in each of the 13 LTNPs.  They identified 6 long-term survivors within the group that had acquired an attenuated strain of HIV-1, transmitted from a single donor, which resulted in slow to non-progression.

After prolonged infection, not all study group members maintained a non-progressive status. The researchers observed differences in CD8 T cell responses and detected increased preservation of helper CD4 T cell responses in elite non-progressors.  They tested the study patients’ anti-HIV T cell function assays by looking at the proliferative responses of CD4 T cells to HIV-1 viral p24 and found that loss of non-progressor status was strongly associated with undetectable or declining responses to viral p24. They also evaluated the capacity of CD8 T cells to respond to and kill HIV infected cells by measuring their ability to produce strong cytokine responses (specifically IFN-γ).  Having strong cytokine responses enables the immune system to target and kill HIV infected cells within the body. They found that strong responses to the viral protein Pol (which is the viral polymerase protein) was key.

The team also looked at CD4 and CD8 T cell responses to other viral proteins.   Historically, the viral envelope protein, gp120, has been the target of the most amount of scientific interest.  But the researchers found that sustained strong responses to the viral protein Gag conferred long term control of viremia.  Specifically, they saw that cellular responses to the majority of this protein’s amino acid sequences were seen in the 3 elite controllers and not in the other LTNP patients.   

Ultimately,  sustained suppression of the virus was found to be associated with preserved T cell proliferative responses to viral protein p24, regardless of the strength and breadth of the cellular responses to other viral antigens. The researchers stated that their study “demonstrated that host and viral genetic factors can contribute to delayed disease progression, but the single immunological factor that functionally defined non-progression was Gag-specific CD4 T cell proliferation” ,  and indicated that the maintenance of this p24-specific response did not require detectable viral replication. 

In conclusion, the authors wrote, “we have demonstrated that a decline in this protective p24 response in slow progressors either preceded or coincided with classic signs of disease progression.”

Retrovirology. 2008; 5: 112.