Immune Based Therapies for HIV Richard Trauger, phd

AN .END. TO.AIDS

Immune Based Therapy For The Treatment Of HIV Infection

Past, Preset and Future

Richard Trauger, PhD

Immune Based Therapy (IBT)

• Active IBT: Designed to turn on an immune response– Vaccines– Ex vivo expansion of immune cells– Cytokines

• Passive IBT: Designed to deliver a specific type of immunity directly into the blood– Antibodies

Evolution of an immune response

Innate immunity is characterized by an Inflammatory response that precedes adaptive immunity

Adaptive Immunity

Increase Titer

Increase CD4 Effectors (helpers)

Increase CD8 effectors (killers)

Vaccines

In The Beginning…

• Anti-viral therapy– Chemical disruption of

the virus replication cycle

• Immune based therapy– Biological disruption of

the virus replication cycle

TIME

Viral Burden?HIV-specific

Immunity

TIME

Viral BurdenHIV-specific Immunity?

Anti-viral drug Treatment

• Clear reduction of viral burden

• Structure Treatment Interruptions showed no recovery of HIV specific immunity

Immune based therapies

• Evidence of activity by recovery of immune functions – Antibodies +++– Cell Mediated Immunity +++– CTL +/-

• Transient improvement in CD4 cell numbers • Marginal to no impact on viral burden

WTF?

• ARV failure to restore immunity– Infection wipes out the HIV immune cells first– Immune exhaustion from prolonged viral infection

• IBT failure to lower viral burden– Immune exhaustion from prolonged viral infection– No clear indication of the immunological function

that could control vial burden

Why The Failures?

“If you don’t know where you’re going any road will get you there.” c.cat

Hyper-Activation and Immunological Exhaustion

• Increased T cell activation is now widely accepted as an important factor in the pathogenesis of HIV.

• Widespread activation-induced death of effector T cells eventually drains the naive and resting memory T cell pools, which eventually leads to immunologic exhaustion

Inflammation

Chronic inflammation as a barrier to IBT • HAART improves CD4 cells count • Not all CD4 cells are equal

– CD4 IL-17 producing cells are lost early

– CD4 IL-17 producing cells control gut bacteria

• Delay in HAART may limit the response to immune based therapy

Elite Controllers

HIV/AIDS • CID 2005:41 Walker Topics in HIV Medicine 2007

Elite control and the Immune Response

Elite controllers provide a unique opportunity to examine the relationship between viral characteristics and host genetics/immune responses in a successful model of durable HIV control without the use of antiretroviral therapy.

Insight gained from these individuals could be used as a platform for studies aimed at therapeutic vaccines and the eradication of HIV.

• Certain HLA class I alleles are enriched in HIV controllers and are associated with strong Gag-specific CD8IFN-IL-2 T cells.

• However, the absence of evidence of T cell-mediated control in many controllers suggests the presence of alternative mechanisms for viral control in these individuals.

• Defining mechanisms for virus control in “non-T-cell controllers” might lead to insights into preventing HIV transmission or preventing virus replication.

The correlates of protection are still to de defined

HIV Controller Consortium

• Extensive viral and host genetic analyses are currently underway through the HIV Controller Consortium, which seeks to enroll 1000 elite controllers and 1000 viremic controllers in order to perform a whole-genome association study to define the genetic basis for this remarkable phenotype.

• This collaborative effort will extend the current study in the hope of defining disease pathways that not only predict durable control of infection but can also lead to new interventions to achieve this state in persons with otherwise-progressive HIV infection.

Lessons from Elite Controllers: HAART and IBT

• Studies of ES have shown that control of fully pathogenic HIV-1 is possible.

• This control typically occurs shortly after primary infection

• Thus one strategy for an effective therapeutic vaccine may be to initiate HAART in primary infection and then to immunize patients to build up an effective adaptive immune response.

Control of HIV-1 Replication in Elite Suppressors. J. Blankson, Discovery Medicine March 24, 2010

ERAMUNE 01: Enrolling people with HIV who are on a fully suppressive ARV regimen and who are judged to have a very small reservoir of infected cells based on a measurement of HIV DNA in the blood.

The study will enroll 28 people living with HIV in Paris, Milan, Barcelona and London. Katlama and her colleagues will add Isentress and Selzentry to everyones regimen, an approach known as treatment intensification, to help maximize control of HIV replication.

Eight weeks after people add Isentress and Selzentry, the research team will give them two cycles of IL-7 injections. The primary aim is to simply decrease the size of the HIV reservoir.

ERAMUNE 02: Overall, 28 HIV-positive patients will have their antiretroviral treatment intensified and will be randomly assigned to either a control or an experimental group.

The experimental group will receive an additional vaccine treatment, in the hopes that this new combination will completely eradicate HIV from the infected individual’s body.

HAART plus Treatment Intensification and IBT

Current IBTs which could be used with HAART

• Active IBT• Autologous

– Dendritic cell vaccines– Redirected Gag specific T Cell Vaccines

• Non-autologous– Viral protein specific CTL inducing vaccines– Polyvalent CTL inducing Vaccines– Neutralizing antibodies – IL-7 stimulation

Role for Passive immunotherapyAIDS Research and Therapy 2009, 6:15

• Anti-LFA-1 antibody (Cytolin)

Summary• A variety of data indicate that risk of transmission of HIV is

markedly reduced at plasma HIV RNA levels below 2000 copies/mL, a level of viremia at which progression of disease is also slowed. (Walker, Topics in Med)

• Elite controllers may provide a direction for the development of an effective immune based therapy– First evidence of immunological control of viral burden– Probably not associated with one type of response

• Intensive HAART plus an effective immune based therapy may provide a therapeutic regimen that can result in long term immune control of the virus