Low level and intermittent HIV replication during very early infection

Low levels of HIV are present in the plasma of individuals during the very early stages of primary HIV infection, according to a United States study published in the June 1^st edition of the Journal of Acquired Immune Deficiency Syndromes. However, the investigators believe that, as viral load at this time is extremely low and yields only transient detectable “blips,” the risk of infection to others is extremely low.

HIV levels increase rapidly from the time viral replication starts and reach a peak coinciding with HIV antibody seroconversion, a process called viral “ramp-up” by the investigators. Calculating HIV viral load during “ramp-up” is an important to allow the development of testing strategies during the window period between exposure to HIV and the development of HIV-specific antibodies.

“Our understanding of the earliest events in primary HIV infection is still evolving”, write the investigators. However, it is accepted that the point at which HIV first becomes detectable in the blood of an individual “marks a crucial time in the point in the natural history of HIV infection because it indicates infectivity of the exposed individual with the potential for secondary transmission.”

The investigators believe that “blips” in HIV viral load during the earliest stages of primary infection are due to “intermittent escape or leakage of small amount of HIV from mucosal and lymphoid tissue near entry sites into the blood stream or from rarer circulating CD4 T-cells.” They believe that this finding has important research and practical implications as it “confirms the capacity for early spread and dissemination of HIV after mucosal penetration, a property that needs to be taken into account in vaccine development and in other strategies for prevention and early treatment.”

Investigators looked for low level viral load (below 100 copies/ml) during the very early stages of primary HIV infection in HIV-positive plasma donations which were provided from 1996 to 1998 at approximately twice-weekly intervals. Plasma donations from 15 panels of donors (total number of donors was 70) were included in the investigators’ analysis.

In nine of the 15 panels of donors, there was no evidence of low level HIV replication preceeding the “ramp-up” phase. When the investigators retested these samples, they found that two donor panels had no low level viraemia. However, in the other seven panels, single plasma donations were found with very low levels of HIV before the first sample was identified with a HIV viral load of 100 copies/ml or more. “We interpret these samples as most likely representing the beginning of the ramp-up phase of viraemia”, write the investigators.

A different pattern of low level HIV replication was observed in the remaining six panels of donors. Five samples were found with very low levels of HIV before “ramp-up.” In addition, eleven samples were identified where transient very low levels of HIV replication were seen before “ramp-up” occurred. These samples were collected a median of 18 days before the first sample with an HIV viral load above 100 copies/ml.

Research in primates suggests that infection through sex with simian immunodeficiency virus (SIV) involves a sequence of events starting with viral penetration of the surface mucosal cell surface, followed by infection of CD4 T-cells , dendritic cells and macrophages below the mucosa before spread to the lymph nodes. Measurable SIV has been detected in plasma five to 30 days after intravaginal exposure and a similar pattern is presumed to exist in humans.

The current study has added to this. The investigators note, “our finding of seemingly random ‘blips’ of low level viraemia occurring up to three weeks before well described dynamic ramp-up phase of six to 15 newly infected source plasma donors suggests that viraemia is not reliably absent during the very early phase of HIV infection.”

Plasma viral load during the “blips” of very early infection were calculated to be between 1 and 10 copies/ml. “This level of viraemia is at least two orders of magnitude lower than the reported threshold of 1500 copies/ml for heterosexual transmission, which makes it doubtful that infected persons would transmit HIV through sexual contact at this very early stage of infection”, comment the investigators. However, they add a caution about the potential infectivity of blood products, noting, “it is conceivable that plasma collected from a newly infected donor during an early viral blip could be infectious when given, for example, as a 200 copies/ml to 250 copies/ml fresh frozen plasma component transfusion or a 50 copies/ml to 400 copies/ml platelet product.” The risk of HIV transmission during very early primary infection is “small” and “theoretic”, the investigators conclude.