The Challenge of HIV

Developing a safe and effective vaccine against HIV is a daunting scientific challenge due to the traits of HIV that allow it to replicate continuously for years in the face of intense host immune responses. In contrast, vaccines tend to be effective against viruses that have evolved to spread to their next host before being eradicated by an effective immune response. HIV’s ability to persistently replicate by evading the immune system makes it an extraordinarily difficult target for vaccines.

Vertebrates, including human beings, have immune systems that specifically recognize the pathogens that we’ve been exposed to in our lifetimes, either through naturally-occurring infection or vaccination. This specific immunity is mediated by antibodies and T cells. Antibodies are soluble protein molecules that circulate in the blood, stick to the viruses they recognize, and physically impede their entry into host cells, thereby blocking infection. Antibodies also can flag virus-infected cells for destruction by the immune system. T cells can recognize and kill virus-infected cells. T cells are also important for supporting the development of immune responses. Antibodies and T cells that recognize specific viruses often can prevent subsequent infection by the viruses we’ve encountered in our lifetimes. 

However, HIV is inherently resistant to both antibody and T cell responses. In order to infect susceptible T cells, HIV needs to fuse the membrane of the virus particle with the membrane of the new host cell, thus depositing the contents of the viral particle, including the viral genome, into the new host cell. The molecular machine of HIV that recognizes and fuses with susceptible T cells is known as “Env.” Most of the surface of Env is inaccessible to antibodies that might otherwise block it from recognizing and infecting T cells, because Env is camouflaged by sugars that are common in our bodies and ignored by the immune system. 

The parts of Env that directly interact with the two viral receptors present on susceptible T cells are buried within deeply recessed cavities that are only accessible by antibodies with unusual features. Furthermore, the parts of Env that recognize each of the two viral receptors are obscured until the other viral receptor is engaged. These features make Env an extraordinarily difficult target for antibodies. HIV also opposes T cell surveillance by interfering with the detection of the viral traces recognized by T cells. Even before considering its ability rapidly mutate and its resulting diversity, HIV is inherently resistant to host immune responses.

Superimposed over this inherent resistance to host immune responses are the extraordinary plasticity and diversity of HIV. Upon infection of a host cell, the HIV genome is copied by a viral enzyme known as reverse transcriptase. Reverse transcriptase has such a high error rate that, on average, a new mutation is introduced each time a new host cell is infected. The high mutation rate of HIV allows it to rapidly generate new progeny viruses that are not recognized by the host antibody or T cell responses. Viral escape occurs so rapidly that it typically appears seamless—the relatively consistent viral loads measured in HIV patients conceal a dynamic, continuous cycle of immune recognition and escape. Continuous cycles of immune recognition, mutation, and viral escape over the century since HIV crossed the species barrier from

chimpanzees has resulted in extraordinary viral diversity among contemporary strains of HIV. The high mutation rate of HIV and resulting viral diversity pose enormous challenges, both for therapy and vaccination.

Because of HIV’s inherent resistance to antibodies, efforts to stimulate antibody responses by vaccination have failed to elicit antibodies that block infection of host cells by typical strains of HIV. It is important to note that the inherent resistance of typical HIV strains to antibodies is the first hurdle that has not yet been overcome, even before we consider HIV’s diversity as a second obstacle. Stimulating an antibody response that can prevent the infection by diverse, inherently antibody-resistant strains of HIV is a daunting challenge that has not yet been achieved by conventional vaccine approaches.