Passive transfer of scrub typhus plasma linked to reduced HIV viral load and clinical improvement

10 April 2002. Related: Basic science and immunology.

Graham McKerrow, HIV i-Base

A clinical study by US army doctors and a local hospital in Thailand has found that the passive transfer of scrub typhus plasma to people with HIV, who were not receiving antiretroviral drugs, was associated with reduced viral load, clinical improvement, a change of phenotype and decreases in CD8+ T cells and IL-6 levels.

Dr George Watt and colleagues safety tested individual 500 mL units of plasma from donors with mild scrub typhus, and subjected the plasma to virucidal heat treatment before administering it to 10 HIV-1 infected recipients. HIV copy numbers fell threefold or more in two recipients, and virus burden was reduced for eight weeks in 70% (7/10) of recipients of a single plasma infusion, compared with the mean of three pre-infusion measurements.

Dr Watt and colleagues from the Retrovirology Department of the US Armed Forces Research Institute of Medical Sciences in Bangkok, the Changrai Regional Hospital, and Human Plasma Product Services in Lille, France, report in the Quarterly Medical Journal of November 2001 [1] that: “In the clearest in vivo response, reduction in viral load was accompanied by clinical improvement, a switchback from the syncytia-inducing to the non-syncytia-inducing phenotype, and decreases in CD8+ T cells and IL-6 levels.

“Scrub typhus infections can generate heat-stable transferable plasma factors that exert prolonged anti-HIV effects. Whether variability in the results is due to different scrub typhus infections, different HIV infections or different individual responses, is unclear”, say the authors.

They also found that scrub typhus donor plasma inhibited HIV-1 in vitro compared with normal human plasma and media controls.

They transferred plasma from patients mildly infected with Orientia tsutsugamushi, the causative agent of scrub typhus, and with no other medical problems. It was given to HIV positive individuals who were not taking antiretrovirals and had <200 CD4+ cells/mm3. Recipients were given slow intravenous infusions of the plasma over two hours, and were monitored closely in hospital for the following 24 hours.

At the same time, complement inactivated plasma from scrub typhus donors was assessed for in vitro inhibition of HIV using cryopreserved peripheral blood mononuclear cells infected with a non-laboratory-adapted Thai strain of clade E virus (NP1668). HIV replication was assessed at three, seven, 10, and 14 days after infection by measuring the amount of p24 antigen in the culture supernatant.

In the in vivo study, the total viral burden during the two months following plasma transfer was established in the five men and five women who received plasma. No significant side effects were reported. The mean increase in bodyweight at one month was 0.8kg and at two months was 1.4kg. One month after infusing, CD4+ T cell counts and haematocrit (volume of red cells in the blood) were significantly higher than pre-infusion values, while white blood cell count was significantly lower.

The authors report that there were no significant changes to CD8+ T cell counts for the 10 plasma recipients as a group. However, there were changes in CD8+ T cell counts at the individual level; one person’s count fell from 1,065 cells/mL before the infusion, to 977 a month after infusion and then to 808 at two months.

Viral load fell dramatically in two recipients. In one the copy number fell from 173,412 copies/mL pre-infusion average to 34,772 at 28 days. In another, the viral load fell from a pre-infusion average of 44,833 to 12,963 at day 35.

In their discussion, the authors report that, “The data from this clinical study support and extend earlier findings [2] that showed HIV-inhibitory effects associated with scrub typhus infection.”

And they write: “The total viral burden during the two months after each plasma transfer was approximated by the AUC (area under the copy number curve). The AUC was less than half that predicted had viral load remained at the pre-infusion level in 7/10 patients.”

Dr Watt and colleagues conclude: “These finding suggest that some scrub typhus plasma contained HIV-inhibitory factors. It is also possible that all plasma contained HIV-suppressor factors but that, for whatever reason, not all subjects responded to them.”

They also draw attention the recipient of plasma whose viral load fell from a pre-infusion average of 166,404 copies/mL to a median value during the two months following plasma infusion of 58,666. This recipient experienced a further threefold fall in viral load following a second plasma infusion. There was also a switchback to the less pathogenic non-syncytia-inducing phenotype, in isolates from this recipient. “One month after receiving the first plasma infusion [this recipient] was able to return to her job in a fruit orchard. A subjective increase in appetite was accompanied by a gain in body weight from 57.0kg pre-infusion to 58.0kg at day 28 and 59.5kg at day 56. IL-6 concentrations fell after plasma was transferred to [her] as occurs with effective antiretroviral therapy.” report Dr Watt and colleagues.

The authors also draw attention in their discussion to the fact that there was no lowering of viral load after plasma transfer to one recipient. And in contrast to the recipient mentioned above, this other recipient experienced an increase in CD8+ T cells.

The authors write that their data suggest that some scrub typhus infections generate heat stable plasma factors capable of exerting anti-HIV effects even in late-stage HIV infection.

And they add: “O. tsutsugamushi infection is common. An estimated one billion people live in endemic areas, and seroprevalence rates of up to 69% have been reported in Thailand. There is therefore a large potential pool of research material with which to further explore possible anti-HIV effects associated with scrub typhus. All scrub typhus plasma were HIV-inhibitory in vitro but, as in natural infection, only some inhibited in vivo.

“The modest increases in weight and haematocrit after the first infusion suggest that the recipients were not harmed and might have benefited from receiving scrub typhus plasma. Plasma with clearly defined in vivo HIV suppressive activity can be used to try to optimise in vitro HIV inhibitory tests and identify an appropriate marker of HIV inhibitory effect. Elucidation of the inhibitory mechanism could generate new tools for the prevention and treatment of HIV infection.”

References:

Watt G, Kantipong P, Jongsakul K et al. Passive transfer of scrub typhus plasma to patients with AIDS: a descriptive clinical study. Q J Med 2001;94:599-607.

Watt G, Kantipong P, deSouza M et al. HIV-1 suppression during acute scrub typhus infection. Lancet 2000; 356:475-9.