. Author manuscript; available in PMC: 2010 Aug 1.

Published in final edited form as: Nat Med. 2009 Aug;15(8):861–865. doi: 10.1038/nm.2013

Table 2. How studies of natural SIV hosts may inform AIDS vaccine development: proposed research priorities.

AIDS prevention strategies	Lessons from natural SIV hosts	Key future research priorities	Potential immunization strategies
Identify neutralizing antibodies in naturally infected primates that target epitopes (for example, CD4 binding site or member-proximal external region) that are highly conserved among primate lentiviruses.	Lifelong nonpathogenic SIV infection may elicit neutralizing antibodies—in the absence of B cell hyperactivation³⁴—that are qualitatively and quantitatively different from those produced in HIV-1 infection.	Assess neutralizing antibody responses in natural SIV infections, determine level of cross-reactivity and define the basis for the lack of B cell hyperactivation.	Design immunoadhesins using components of SIV-specific neutralizing antibodies from naturally infected species and deliver them to mucosal surfaces using vectors (for example, adeno-associated virus vector).

Induce virus-specific cellular immune responses that can delay disease progression.	SIV-specific T cell responses are similar in magnitude and breadth but are not associated with bystander T cell activation¹⁸,²⁷–²⁹,³⁰.	Identify the link between SIV-specific T cell responses and T cell hyperactivation in pathogenic and nonpathogenic HIV and SIV infections.	Develop immunization approaches that induce strong HIV-specific T cell responses without inducing long-term, chronic-stage bystander T cell activation.

Maximize the antiviral activity of innate immune responses using vaccine adjuvants.	Innate immune responses and type I interferon responses are robust in acute but not chronic infection¹³–¹⁹,³⁷.	Define the mechanisms by which innate immune responses to SIV are rapidly downmodulated in natural SIV hosts.	Develop adjuvants that, when coupled with an immunogen, result in strong but transient innate immune responses to HIV.

Decrease the availability of CD4⁺CCR5⁺ target cells at the site of virus transmission.	Natural SIV hosts express low amounts of CCR5 on CD4⁺ T cells⁴¹,⁴². AGMs downmodulate CD4 expression upon T cell activation⁴⁵.	Elucidate the mechanisms underlying the differing expression of CD4, CCR5 or both in natural SIV hosts.	Couple CCR5 antagonists with immunogens to induce HIV-specific responses that are independent of activated CD4⁺CCR5⁺ T cells at mucosal tissues.

Reduce the level of chronic immune activation in the event of breakthrough infection.	Elevated immune activation in acute infection is rapidly downregulated during chronic infection¹⁵,¹⁸,⁴². Natural SIV hosts preserve mucosal immunity and gut T_H17 cells and avoid microbial translocation despite depletion of mucosal CD4⁺ T cells¹⁶,¹⁷,³²,³⁷. HIV-1 Nef has lost the ability to downmodulate CD3–T cell receptor expression⁴⁶.	Identify the mechanisms responsible for the lack of chronic immune activation in natural SIV hosts: immunomodulatory pathways (T regulatory cells, the negative regulator PD-1 and transforming growth factor-β, among others); specific virus proteins (Nef, Vpu and Env); and preserved mucosal immunity and lack of microbial translocation. Assess species-specific differences in innate and adaptive responses to SIV.	Develop immunogens that have built-in factors to prevent the development of chronic immune activation in the event of HIV infection. Develop immunization approaches that stimulate the negative control of inflammation in the event of HIV infection.

Prevent mother-to-child transmission (MTCT).	MTCT of SIV is rare in natural SIV hosts³⁸–⁴⁰.	Define the mechanisms underlying the partial resistance to MTCT in natural SIV hosts (maternal or fetal antiviral factors; role of low CCR5 expression and CD4 downmodulation).	Develop immunogenic approaches that mimic the mechanisms underlying the relative resistance to MTCT in natural SIV hosts.