In the first part, I introduced the Dendritic Cells (DCs) as immune sentries entrusted with a surveillance function, and mentioned how HIV is able to subvert the normal functions of DCs and and use them as Trojan Horses to infect CD4+ helper T-cells. I also referred to a 2009 study which discovered a possible involvement of certain membrane lipids in the process of DC-mediated HIV trans-infection of T-cells.

A recent (2011) study by Boasso et al. 1 on plasmacytoid DCs (pDCs) builds further on this matter. In response to TLR engagement, whereas myeloid DCs (mDCs) produce IL12, pDCs secrete high levels of Type I Interferons (IFNα and β). In the early phases of viral infections, Type I Interferons are critical, expressing their antiviral function by inhibiting proliferation of—and inducing cell-death (apoptosis) in—multiple types of infected cells, including T-cells.

Therefore, it is understandable that if, for some reason, the activation of pDC and consequent Type I Interferon release become chronic and sustained, it impairs the immune system by promoting excessive T-cell death and interfering with antigen-specific T-cell responses. It is known that HIV is a strong and direct activator of pDCs, through the interaction between HIV gp120 and CD4 molecule on the surface of pDCs.

Analogous to the membrane microdomains in exosome-producing cells (that I mentioned in the first part), the HIV envelope contains microdomains of tightly-packed cholesterol (IOW, fat love-handles!), and these are the areas postulated to be involved in HIV-pDC contact. Reduction of the cholesterol in HIV envelope by chemical means renders the virus non-infective (References in the Boasso paper).

In their study, Boasso and his colleagues from the Imperial College London, Aquino and Graham of the Johns Hopkins University School of Medicine, Baltimore, and other collaborators from Italy and Austria, used a technique by which the HIV envelope could be chemically depleted of its cholesterol content to varying degrees, with maximum depletion resulting in permeabilization of the HIV envelope with loss of the viral capsid protein p24. However, the preparations retained the p55 gag polyprotein, as well as the envelope glycoprotein gp120 (through which HIV interacts with DCs and T-cells). On the other hand, there was some loss of the viral RNA. (N.B. All these are important considerations for subsequent experiments, which would test the ability of the envelope-modified virus to infect.)

The experiments elegantly demonstrated that:

  • HIV with a cholesterol-depleted or permeabilized envelope had reduced or nullified ability to induce Type 1 interferons compared to untreated HIV, even at the same viral RNA concentrations.
  • The envelope-modified virus retained its ability to increase the expression of the costimulatory molecule CD80 (signal necessary for T-cell activation) in pDCs and monocytes, but…
  • Permeabilization completely abrogated its ability to promote the expression of T-cell activation markers (such as, CD83; usually associated with HIV-disease progression) in pDCs, mDCs and monocytes.
  • Cholesterol-depletion and permeabilization both significantly reduced the uptake of the virus by pDCs, mDCs and monocytes.
  • In addition, envelope permeabilization also relieved HIV-induced pDC-mediated immunosuppression (that occurs through negative regulation of T-cells and CD4+ T-cell apoptosis via immunomodulatory Type 1 Interferons), even though pDCs were partially activated. This bodes well for the host, since it indicates the beneficial effects of pDC activation may be dissociated from the harm caused by over-activation.
  • Envelope-modified HIV was able to boost HIV-specific memory CD8+ T-cell responses in HIV-exposed seronegative individuals, i.e. in presence of pre-existing immunity, and to a lesser extent in HIV-infected patients. This observation—found to be related to the inability of the permeabilized HIV to induce Type 1 interferons—is significant, since it means that envelope-modified HIV can serve as a powerful recall antigen, stimulating antiviral Interferon γ, in HIV-exposed individuals.

One important caveat which the authors observed relates to the differences in lipid composition and envelope organization of different HIV-1 isolates. Using two different isolates, they noted slightly different observations. However, overall, cholesterol withdrawal—and resultant envelope integrity loss—affected the ability of all HIV-1 isolates to activate pDCs. Although the observations suggest that there may be other non-envelope viral components (such as the oligosaccharide component of viral glycoproteins), which can lead to alternative activation of antigen-presenting cells (such as pDCs), envelope-modification of HIV may eliminate the deleterious effects of immune over-activation while focusing the beneficial ones that would result in the maintenance of an efficient memory T-cell response leading to the clearance or long-term control of HIV infection.

In other words, getting rid of HIV’s fat love-handles (a leaner HIV!) can help boost an immune system that has already encountered the virus. This may open up awesome possibilities for a rational vaccine design for long-term HIV control.

Further reading:

1. Boasso, A., Royle, C., Doumazos, S., Aquino, V., Biasin, M., Piacentini, L., Tavano, B., Fuchs, D., Mazzotta, F., Lo Caputo, S., Shearer, G., Clerici, M., & Graham, D. (2011). Over-activation of plasmacytoid dendritic cell inhibits anti-viral T-cell responses: a model for HIV immunopathogenesis Blood DOI: 10.1182/blood-2011-03-344218 (PMID: 21931112)